L6.0 Immune recognition molecule (MHC,T cell receptor, T cell epitopes, T cell markers, B cell epitopes, Toll like receptors) 19 may2023.pptx

DEPARTMENT OF MICROBIOLOGY AND
IMMUNOLOGY
IMMUNE RECOGNITION MOLECULES (MHC, T-
CELL RECEPTORS, T-CELL EPITOPES, T CELL
MARKERS, B CELL EPITOPES, TOLL LIKE
RECEPTORS)
Facilitator: DR S. S. MASOUD
Presenter: Victoria Shayo
Venue: Microbiology Lab
Date: 29/05/2023
6/18/2023 Vickie 1
Learning Outcomes
• Describe IMMUNE RECOGNITION MOLECULES
• Explain MHC, T-CELL RECEPTORS, T-CELL EPITOPES, T
CELL MARKERS, B CELL EPITOPES, TOLL LIKE
RECEPTORS
Vickie
6/18/2023 2
Outlines
• Introduction
• Major Histocompatibility Complex
• T-cell receptors
• T-cell epitopes
• T-cell Markers
• B-cell epitopes
• Toll-like Receptors
6/18/2023 Vickie 3
Introduction
IMMUNE RECOGNITION MOLECULE(IRM)
These are the major proteins of the
immune system.
Before any immune mechanism can go
into action, there must be a recognition
that something exists for it to act against
6/18/2023 Vickie 4
Forms of IRM
Soluble molecules including Cytokines,
Interleukins, antibodies, Complements and
metabolites.
Cell membrane associated including
markers (CD), receptors (BCR, TCR,
MHCI, MHCII etc.), co stimulatory
molecules e.g. B7 family on DCs
,adhesion molecules (integrins, selectins,
mucins, etc.) and Tumour markers e.g
CEA 125
6/18/2023 Vickie 5
The immune recognition and receptors in innate
and adaptive immunity
6/18/2023 Vickie 6
6/18/2023 Vickie 7
6/18/2023 Vickie 8
Major Histocompatibility Complex
• The major histocompatibility complex (MHC) is a large
locus on vertebrate DNA containing a set of closely
linked polymorphic genes that code for cell surface
proteins essential for the adaptive immune system.
• The major histocompatibility complex is located on
chromosome 6 in humans and extends over some 4
centimorgans of DNA, about 4 × 106 base pairs.
• In humans it contains more than 224 genes, and about
half have known immune functions
6/18/2023 Vickie 9
Major Histocompatibility Complex
• The genes encoding the α chains of MHC class I molecules
and the α and β chains of MHC class II molecules are linked
within the complex.
• In humans these genes are called Human Leukocyte Antigen or
HLA genes, as they were first discovered through antigenic
differences between white blood cells from different individuals.
6/18/2023 Vickie 10
Expression of MHC Molecules
• Because MHC molecules are required to present
antigens to T lymphocytes, the expression of these
proteins in a cell determines whether foreign antigens in
that cell will be recognized by T cells.
• There are several important features of the expression
of MHC molecules that contribute to their role in
protecting individuals from different microbial infections.
6/18/2023 Vickie 11
Expression of MHC Molecules
 Class I molecules are expressed on virtually all nucleated cells, whereas
class II molecules are expressed only on dendritic cells, B lymphocytes,
macrophages, thymic epithelial cells, and a few other cell types.
 MHC I displays endogenous antigens, or antigens from within the cell, while
MHC II displays exogenous antigens, or antigens from outside the cell.
These outside antigens are obtained by way of phagocytosis, so only
phagocytes in the body have MHC-2.
 CD8+ CTLs kill cells infected with intracellular microbes, such as viruses,
as well as tumours that express tumor antigens, and any nucleated cell
can harbour a virus or develop into cancer.
 In contrast, class II–restricted CD4+ helper T lymphocytes have a set of
functions that require recognizing antigen presented by a more limited
number of cell types, and class II molecules are expressed mainly on
these cell types, for the following reasons.
6/18/2023 Vickie 12
Expression of MHC Molecules
 The expression of MHC molecules is increased by cytokines produced
during both innate and adaptive immune responses.
 Although class I molecules are constitutively expressed on nucleated cells, their
expression is increased by the type I interferons IFN-α and IFN-β, which are
produced during the early innate immune response to many viruses.
 The expression of class II molecules is regulated by cytokines and other signals
in different cells. IFN-γ is the principal cytokine involved in stimulating expression
of class II molecules in APCs such as DCs and macrophages.
 B lymphocytes constitutively express class II molecules and can increase
expression in response to antigen recognition and cytokines produced by helper
T cells, thus enhancing antigen presentation to helper cells .
6/18/2023 Vickie 13
Expression of MHC Molecules
 The rate of transcription is the major determinant of the level of MHC
molecule synthesis and expression on the cell surface.
 Cytokines enhance MHC expression by stimulating the transcription of class I
and class II genes in a wide variety of cell types. These effects are mediated by
the binding of cytokine-activated transcription factors to DNA sequences in the
promoter regions of MHC genes.
 Several transcription factors may be assembled and bind a protein called the
class II transcription activator (CIITA), which is a member of the NOD-like
receptor family, and the entire complex binds to the class II promoter and
promotes efficient transcription of the gene.
6/18/2023 Vickie 14
General Properties of MHC Molecules
Each MHC molecule consists of an extracellular peptide-
binding cleft, followed by an immunoglobulin (Ig)–like
domain and transmembrane and cytoplasmic domains.
Class I molecules are composed of one polypeptide
chain encoded in the MHC and a second, non-
MHC–encoded chain, whereas class II molecules
are made up of two MHC-encoded polypeptide
chains.
Despite this difference, the overall three-
dimensional structures of class I and class II
molecules are similar.
6/18/2023 Vickie 15
General Properties of MHC Molecules
The polymorphic amino acid residues of
MHC molecules are located in and
adjacent to the peptide-binding cleft.
 This cleft is formed by the folding of the
amino termini of the MHC-encoded proteins
and is composed of paired α helices forming
the two walls of the cleft, resting on a floor
made up of an eight-stranded β-pleated
sheet.
 This portion of the MHC molecule binds
peptides for display to T cells, and the
antigen receptors of T cells interact with the
displayed peptide and also with the α helices
of the MHC molecules.
6/18/2023 Vickie 16
General Properties of MHC Molecules
 The nonpolymorphic Ig-like domains of class II and class I MHC
molecules contain binding sites for the T cell molecules CD4 and
CD8, respectively.
 CD4 and CD8 are expressed on distinct subpopulations of mature T
lymphocytes and participate, together with antigen receptors, in the
recognition of antigen.
 CD4 binds selectively to class II MHC molecules, and CD8 binds to class
I molecules.
 This is why CD4+ helper T cells recognize class II MHC molecules
displaying peptides, whereas CD8+ T cells recognize class I MHC
molecules with bound peptides..
6/18/2023 Vickie 17
Class I MHC Molecules
• Class I MHC molecules consist
of two noncovalently linked
polypeptide chains, an MHC-
encoded α chain (or heavy
chain) and a non-MHC–
encoded subunit called β2-
macroglobulin.
• The amino-terminal α1 and α2
segments of the α chain interact
to form a platform of an eight-
stranded, antiparallel β-pleated
sheet supporting two parallel
strands of α helix.
6/18/2023 Vickie 18
Class I MHC Molecules
• This forms the peptide-binding cleft of class I molecules.
Its size is large enough to bind peptides of 8 to 11 amino
acids in a flexible, extended conformation.
• The α3 segment of the α chain folds into an Ig domain
whose amino acid sequence is conserved among all
class I MHC molecules.
• This segment contains most of the binding site for CD8,
but β2-microglobulin and a small part of the
nonpolymorphic C-terminal portion of the α2 domain
also contribute.
6/18/2023 Vickie 19
Class I MHC Molecules
• The fully assembled class I molecule is a trimeric
complex consisting of an α chain, β2-microglobulin, and
a bound peptide, and stable expression of class I
molecules on cell surfaces requires the presence of all
three components of the complex.
• Most individuals are heterozygous for MHC genes and
therefore express six different class I molecules on
every cell, containing α chains encoded by the two
inherited alleles of HLA-A, B, and C genes.
6/18/2023 Vickie 20
Class II MHC Molecules
• Class II MHC molecules are
composed of two noncovalently
associated polypeptide chains, a
32- to 34-kD α chain, and a 29- to
32-kD β chain.
• Unlike class I molecules, the genes
encoding both chains of class II
molecules are polymorphic and
located in the MHC locus.
• The amino-terminal α1 and β1
segments of the class II chains
interact to form the peptide-binding
cleft, which is structurally similar to
the cleft of class I molecules.
6/18/2023 Vickie 21
Class II MHC Molecules
• The ends of the peptide-binding cleft of class II
MHC molecules are open, so peptides of 30
residues or more can bind.
• The α2 and β2 segments of class II MHC
molecules, like class I α3 and β2-microglobulin,
are folded into Ig domains and are
nonpolymorphic—that is, they do not vary among
alleles of a particular class II gene.
• Both the α2 and β2 domains of class II molecules
contribute to a concavity that accommodates a
protrusion of the CD4 protein, thus allowing
binding to occur.
6/18/2023 Vickie 22
Class II MHC Molecules
• The fully assembled class II MHC molecule is a trimer
consisting of one α chain, one β chain, and a bound
antigenic peptide, and stable expression of class II
molecules on cell surfaces requires the presence of all
three components of the complex.
• Humans inherit, from each parent, one DPA and one
DPB gene encoding, respectively, the α and β chains of
an HLA-DP molecule; one functional DQA and one DQB
gene; one DRA and one or two functional DRB genes.
• Thus, each heterozygous individual expresses six to
eight pairs of class II MHC α and β chain molecules, one
set each of DP and DQ, and one or two of DR.
6/18/2023 Vickie 23
Features of Class I and Class II MHC Molecules
6/18/2023 Vickie 24
Features of Class I and Class II MHC Molecules
Cont…..
6/18/2023 Vickie 25
Binding of Peptides To MHC
 Characteristics of Peptide-MHC Molecule Interactions
• MHC molecules show a broad specificity for peptide binding, in
contrast to the fine specificity of antigen recognition by the antigen
receptors of lymphocytes.
• In other words, a single MHC allele (e.g., HLA-A2) can present any
one of many different peptides to T cells, but a single T cell will
recognize only one of these many possible HLA-A2/peptide
complexes.
• There are several important features of the interactions of MHC
molecules and antigenic peptides.
6/18/2023 Vickie 26
Binding of Peptides To MHC
6/18/2023 Vickie 27
6/18/2023 Vickie 28
Binding of Peptides To MHC
Each class I or class II MHC molecule has a
single peptide-binding cleft that binds one
peptide at a time, but each MHC molecule can
bind many different peptides.
It is not surprising that a single MHC molecule
can bind multiple peptides, because each
individual contains only a few different MHC
molecules and these must be able to present
peptides from the enormous number of protein
antigens that one is likely to encounter.
6/18/2023 Vickie 29
Binding of Peptides To MHC
The peptides that bind to MHC molecules share
structural features that promote this interaction.
 One of these features is the size of the peptide—class I
molecules can accommodate peptides that are 8 to 11
residues long, and class II molecules bind peptides that
may be 10 to 30 residues long or longer, the optimal
length being 12 to 16 residues.
 In addition, peptides that bind to a particular MHC
molecule contain amino acid residues that allow
complementary interactions between the peptide and
that MHC molecule.
 The residues of a peptide that bind to MHC molecules
are distinct from those that are recognized by T cells.
6/18/2023 Vickie 30
Binding of Peptides To MHC
MHC molecules acquire their peptide cargo during
their biosynthesis and assembly inside cells.
Therefore, MHC molecules display peptides
derived from microbial antigens that are inside host
cells, and this is why MHC-restricted T cells are
able to recognize microbes that infect or are
ingested into cells.
Importantly, class I MHC molecules acquire
peptides from cytosolic proteins that are digested
into peptides by a cytosolic enzyme complex, and
class II molecules acquire peptides from
extracellular proteins that are ingested into and
digested in endocytic vesicles.
6/18/2023 Vickie 31
Binding of Peptides To MHC
The association of peptides and MHC molecules is a
saturable interaction with a very slow off-rate.
 In a cell, several chaperones and enzymes facilitate the
binding of peptides to MHC molecules.
 Once formed, most peptide-MHC complexes are stable,
and kinetic dissociation constants are indicative of long
half-lives that range from hours to many days.
 This extraordinarily slow off-rate of peptide dissociation
from MHC molecules ensures that after an MHC
molecule has acquired a peptide, it will display the
peptide long enough to maximize the chance that a
particular T cell will find the peptide it can recognize and
initiate a response.
6/18/2023 Vickie 32
Binding of Peptides To MHC
 Very small numbers of peptide-MHC complexes are capable of
activating specific T lymphocytes.
 Because APCs continuously present peptides derived from all the
proteins they encounter, only a very small fraction of cell surface
peptide–MHC complexes will contain the same peptide.
 It has been estimated that as few as 100 complexes of a particular
peptide with a class II MHC molecule on the surface of an APC can
initiate a specific T cell response.
 This represents less than 0.1% of the total number of class II
molecules likely to be present on the surface of the APC.
6/18/2023 Vickie 33
Binding of Peptides To MHC
The MHC molecules of an individual can bind and
display foreign peptides (e.g., those derived from
microbial proteins) as well as peptides derived from the
proteins of that individual (self antigens)
 In fact, most of the peptides being displayed normally by
APCs are derived from self proteins.
 Self peptide–MHC complexes do not induce
autoimmunity because T cells specific for such
complexes are killed or inactivated.
 In fact, T cells with receptors for self antigens must
recognize self peptides displayed by self MHC
molecules in order to be eliminated or made
unresponsive. These processes ensure that T cells are
normally tolerant to self antigens.
6/18/2023 Vickie 34
The Phenomenon Of MHC Restriction
The formal proof that the MHC is involved in
antigen recognition by T cells came from the
experimental demonstration of MHC restriction by
Rolf Zinkernagel and Peter Doherty.
Thus, T cells must be specific not only for the
antigen but also for MHC molecules, and T cell
antigen recognition is restricted by the MHC
molecules a T cell sees.
Subsequent studies established that the
recognition of antigens by CD8+ CTLs is restricted
by class I MHC molecules, and the responses of
CD4+ helper T lymphocytes to antigens are
restricted by class II MHC molecules.
6/18/2023 Vickie 35
The Phenomenon Of MHC Restriction
6/18/2023 Vickie 36
T-cell Receptors
• Protein complex found on the surface of T Lymphocytes
that is responsible for recognizing fragments of antigens
as peptides bound to major histocompatibility complex
molecules.
• The practical function of these receptors is to enable a
T‐cell to probe the surfaces of cells looking for nonself
peptides.
 If a T‐cell finds a peptide–MHC combination that is a good
match for its TCR it will become activated, undergo clonal
expansion, and differentiate to a mature effector T‐cell capable
of joining the fight against the infectious agent generating these
nonself peptides.
6/18/2023 Vickie 37
T-cell Receptors
Structure:
 The antigen receptor is a heterodimer consisting of two
transmembrane polypeptide chains, designated TCR α and
β, covalently linked to each other by a disulfide bridge
between extracellular cysteine residues.
 Each TCR α and β chain consists of one Ig-like N-terminal
variable (V) domain, one Ig-like constant (C) domain, a
hydrophobic transmembrane region, and a short cytoplasmic
region.
 Thus, the extracellular portion of the TCR αβ heterodimer is
structurally similar to the antigen-binding fragment (Fab) of
an Ig molecule, which is made up of the V and C regions of a
light chain and the V region and the first C region of a heavy
chain.
6/18/2023 Vickie 38
T-cell Receptors
6/18/2023 Vickie 39
Structure of the T-cell Receptor:
T-cell Epitopes
• T-cell epitopes are peptides derived from antigens and
recognized by the TCR when bound to MHC molecules
displayed on the cell surface of APCs.
• CD4 T-cells express the CD4 coreceptor, which binds to
MHC II, and recognize peptides presented by MHC II
molecules.
• CD8 T-cells express the CD8 coreceptor, which binds to
MHC I, and recognize peptides presented by MHC I
molecules.
• T cell epitopes presented by MHC class I molecules are
typically peptides between 8 and 11 amino acids in
length whereas MHC class II molecules present 13-17
a.acids.
6/18/2023 Vickie 40
Function of T cell receptor
What Does the αβ T Cell Receptor (TCR)
Recognize?
• Only fragments of proteins (peptides)
associated with MHC molecules on
surface of cells
• Helper T cells (Th) recognize peptide
associated with MHC class II molecules
• Cytotoxic T cells (Tc) recognize peptide
associated with MHC class I molecules
6/18/2023 Vickie 41
T-cell Epitopes
T-cell
epitope
recognit
ion
6/18/2023 Vickie 42
T-cell Markers
• Is a group of cell surface protein marker on the
white blood cells used to classify immune cell
types and establish international nomenclature
standards.
• The markers are found on many blood cells and
are most often used to refer Lymphocytes,
• The system of assigning markers is intended for
classification of many monoclonal antibodies
generated by different laboratories around the
world against epitopes on the surface
molecules of leukocytes.
6/18/2023 Vickie 43
T-cell Markers
Designation/Nomenclature
These cell surface markers are designated by
prefix CD followed by a number. The number
reflect the order in which the cell surface
marker was discovered.
At present it ranges from CD1 to CD371. It is
useful in identifying many different types of
Leukocytes.
It tells about cell lineage, species to which cell
belong, stage of maturation or activation of the
cell.
6/18/2023 Vickie 44
B-cell Epitopes
• Antigen-antibody interaction is a key event in
humoral immune response to invading pathogen.
• A specific antibody (Ab) recognizes antigen (Ag)
at discrete regions known as antigenic
determinants or B-cell epitopes.
• B-cell epitopes can be defined as a surface
accessible clusters of amino acids, which are
recognized by secreted antibodies or B-cell
receptors and are able to elicit cellular or humoral
immune response
6/18/2023 Vickie 45
B-cell Epitopes
• B-cell epitopes are
solvent-exposed
portions of the
antigen that bind to
secreted and cell-
bound Igs.
• B-cell receptors
encompass cell-
bound Igs, consisting
of two heavy chains
and two light chains.
• The different chains
and regions are
annotated.
B-cell epitope
6/18/2023 Vickie 46
B-cell Epitopes
• Based on the spatial structure B-cell epitopes
can be categorized as;
– a continuous (linear or sequential) and
– discontinuous (nonlinear or conformational)
epitopes;
• in the latter case amino acid residues are in
close contact due to the three-dimensional
conformation.
• Antibodies are developed to bind the epitope
with high affinity by using complementary
determining regions (CDRs).
6/18/2023 Vickie 47
Function of B Cell
What Does The B Cell Immunoglobulin
(Ig) Receptor Recognize?
• Proteins (conformational determinants,
denatured or proteolyzed determinants)
• Nucleic acids
• Polysaccharides
• Some lipids
• Small chemicals (haptens)
6/18/2023 Vickie 48
Toll-like Receptors
• Toll-like receptors (TLRs) are an evolutionarily
conserved family of pattern recognition receptors
expressed on many cell types that recognize products of
a wide variety of microbes, as well as molecules
expressed or released by stressed and dying cells.
• Named on the basis of their similarity to the Toll receptor
in the fruit fly, Drosophila.
• There are 10 expressed TLR genes in humans and each
is devoted to recognizing a distinct set of molecular
patterns that are not found in healthy vertebrate cells.
6/18/2023 Vickie 49
Toll-like Receptors
Structure
 All TLRs have the same basic structural features, with
multiple N‐terminal leucine‐rich repeats (LRRs)
arranged in a horseshoe‐ or crescent‐shaped solenoid
structure that acts as the PAMP‐binding domain.
 All mammalian TLR proteins have a TIR (for Toll-IL-l
receptor) domain in their cytoplasmic tail, which
interacts with other TIR-type domains, usually in other
signalling molecules.
6/18/2023 Vickie 50
Toll-like Receptors
Structure
6/18/2023 Vickie 51
Toll-like Receptors
Location
 TLRs are found on the cell surface and on intracellular
membranes and are thus able to recognize microbes in
different cellular locations.
 TLRs 1, 2, 4, 5, and 6 are expressed on the plasma
membrane, where they recognize various PAMPs in the
extracellular environment.
 In contrast, TLRs 3, 7, 8, and 9 are mainly expressed
inside cells on endoplasmic reticulum and endosomal
membranes, where they detect several different
microbial nucleic acids.
6/18/2023 Vickie 52
Toll-like Receptors
Location
The cellular locations of the mammalian Toll-like receptors
6/18/2023 Vickie 53
Toll-like Receptors
Ligands
 Mammalian TLRs are involved in responses to a wide
variety of molecules that are expressed by microbes
but not by healthy mammalian cells.
 The ligands that the different TLRs recognize are
structurally diverse and include products of all classes
of microorganisms.
– Examples of bacterial products that bind to TLRs are the
bacterial cell wall constituents (LPS and lipoteichoic acid),
flagellin, a protein subunit component of the flagella of motile
bacteria.
– Examples of nucleic acids that are TLR ligands are double-
stranded RNAs, single-stranded RNAs, and unmethylated
CpG dinucleotides
6/18/2023 Vickie 54
6/18/2023 Vickie 55
Toll-like Receptors
• Upon binding of a PAMP, TLRs transduce signals into
the cell via their TIR domains, which recruit adaptor
proteins within the cytoplasm that possess similar TIR
motifs.
• These adaptors propagate the signal downstream,
culminating in activation of NFκB and interferon
regulatory family (IRF) transcription factors (AP-1, IRF3,
and IRF7).
• NF-κB and AP-1 stimulate the expression of genes
encoding many of the molecules required for
inflammatory responses, including inflammatory
cytokines (TNF and IL-1), chemokines (CCL2 and
CXCL8), and endothelial adhesion molecules ( E-
selectin).
6/18/2023 Vickie 56
Toll-like Receptors
• IRF3 and IRF7 promote production of type I interferons
(IFN-α and IFN-β), which are important for antiviral
innate immune responses.
• Different combinations of adaptors and signaling
intermediates are used by different TLRs, accounting for
the common and unique downstream effects of the
TLRs.
• For example, cell surface TLRs that engage the adaptor
MyD88 lead to NF-κB activation, and TLR signaling that
uses the adaptor called TRIF (TIR domain– containing
adaptor inducing IFN-β) leads to IRF3 activation.
6/18/2023 Vickie 57
Toll-like Receptors
6/18/2023 Vickie 58
REFERENCES
1. Delves, P., Martin, S., Burton, D. and Roitt, I., 2017. Roitt's essential
immunology. 13th ed. Oxford: WILEY Blackwell, pp.23-24.
2. Potocnakova, L., Bhide, M., & Pulzova, L. B. (2016). An Introduction to B-
Cell Epitope Mapping and In Silico Epitope Prediction. Journal of
immunology research, 2016, 6760830.
https://doi.org/10.1155/2016/6760830
3. Abbas, A., Lichtman, A. and Pillai, S., 2018. Cellular and molecular
immunology. 9th ed. Philadelphia: ELSEVIER.
4. Kenneth, M., Weaver, C. and Janeway, C., 2017. Janeway's
immunobiology. 9th ed. New York: Garland Science.
5. Handbook of Systemic Autoimmune Diseases, 2017
6/18/2023 Vickie 59
•THANK
YOU
6/18/2023 Vickie 60
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L6.0 Immune recognition molecule (MHC,T cell receptor, T cell epitopes, T cell markers, B cell epitopes, Toll like receptors) 19 may2023.pptx

  • 1. DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY IMMUNE RECOGNITION MOLECULES (MHC, T- CELL RECEPTORS, T-CELL EPITOPES, T CELL MARKERS, B CELL EPITOPES, TOLL LIKE RECEPTORS) Facilitator: DR S. S. MASOUD Presenter: Victoria Shayo Venue: Microbiology Lab Date: 29/05/2023 6/18/2023 Vickie 1
  • 2. Learning Outcomes • Describe IMMUNE RECOGNITION MOLECULES • Explain MHC, T-CELL RECEPTORS, T-CELL EPITOPES, T CELL MARKERS, B CELL EPITOPES, TOLL LIKE RECEPTORS Vickie 6/18/2023 2
  • 3. Outlines • Introduction • Major Histocompatibility Complex • T-cell receptors • T-cell epitopes • T-cell Markers • B-cell epitopes • Toll-like Receptors 6/18/2023 Vickie 3
  • 4. Introduction IMMUNE RECOGNITION MOLECULE(IRM) These are the major proteins of the immune system. Before any immune mechanism can go into action, there must be a recognition that something exists for it to act against 6/18/2023 Vickie 4
  • 5. Forms of IRM Soluble molecules including Cytokines, Interleukins, antibodies, Complements and metabolites. Cell membrane associated including markers (CD), receptors (BCR, TCR, MHCI, MHCII etc.), co stimulatory molecules e.g. B7 family on DCs ,adhesion molecules (integrins, selectins, mucins, etc.) and Tumour markers e.g CEA 125 6/18/2023 Vickie 5
  • 6. The immune recognition and receptors in innate and adaptive immunity 6/18/2023 Vickie 6
  • 9. Major Histocompatibility Complex • The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. • The major histocompatibility complex is located on chromosome 6 in humans and extends over some 4 centimorgans of DNA, about 4 × 106 base pairs. • In humans it contains more than 224 genes, and about half have known immune functions 6/18/2023 Vickie 9
  • 10. Major Histocompatibility Complex • The genes encoding the α chains of MHC class I molecules and the α and β chains of MHC class II molecules are linked within the complex. • In humans these genes are called Human Leukocyte Antigen or HLA genes, as they were first discovered through antigenic differences between white blood cells from different individuals. 6/18/2023 Vickie 10
  • 11. Expression of MHC Molecules • Because MHC molecules are required to present antigens to T lymphocytes, the expression of these proteins in a cell determines whether foreign antigens in that cell will be recognized by T cells. • There are several important features of the expression of MHC molecules that contribute to their role in protecting individuals from different microbial infections. 6/18/2023 Vickie 11
  • 12. Expression of MHC Molecules  Class I molecules are expressed on virtually all nucleated cells, whereas class II molecules are expressed only on dendritic cells, B lymphocytes, macrophages, thymic epithelial cells, and a few other cell types.  MHC I displays endogenous antigens, or antigens from within the cell, while MHC II displays exogenous antigens, or antigens from outside the cell. These outside antigens are obtained by way of phagocytosis, so only phagocytes in the body have MHC-2.  CD8+ CTLs kill cells infected with intracellular microbes, such as viruses, as well as tumours that express tumor antigens, and any nucleated cell can harbour a virus or develop into cancer.  In contrast, class II–restricted CD4+ helper T lymphocytes have a set of functions that require recognizing antigen presented by a more limited number of cell types, and class II molecules are expressed mainly on these cell types, for the following reasons. 6/18/2023 Vickie 12
  • 13. Expression of MHC Molecules  The expression of MHC molecules is increased by cytokines produced during both innate and adaptive immune responses.  Although class I molecules are constitutively expressed on nucleated cells, their expression is increased by the type I interferons IFN-α and IFN-β, which are produced during the early innate immune response to many viruses.  The expression of class II molecules is regulated by cytokines and other signals in different cells. IFN-γ is the principal cytokine involved in stimulating expression of class II molecules in APCs such as DCs and macrophages.  B lymphocytes constitutively express class II molecules and can increase expression in response to antigen recognition and cytokines produced by helper T cells, thus enhancing antigen presentation to helper cells . 6/18/2023 Vickie 13
  • 14. Expression of MHC Molecules  The rate of transcription is the major determinant of the level of MHC molecule synthesis and expression on the cell surface.  Cytokines enhance MHC expression by stimulating the transcription of class I and class II genes in a wide variety of cell types. These effects are mediated by the binding of cytokine-activated transcription factors to DNA sequences in the promoter regions of MHC genes.  Several transcription factors may be assembled and bind a protein called the class II transcription activator (CIITA), which is a member of the NOD-like receptor family, and the entire complex binds to the class II promoter and promotes efficient transcription of the gene. 6/18/2023 Vickie 14
  • 15. General Properties of MHC Molecules Each MHC molecule consists of an extracellular peptide- binding cleft, followed by an immunoglobulin (Ig)–like domain and transmembrane and cytoplasmic domains. Class I molecules are composed of one polypeptide chain encoded in the MHC and a second, non- MHC–encoded chain, whereas class II molecules are made up of two MHC-encoded polypeptide chains. Despite this difference, the overall three- dimensional structures of class I and class II molecules are similar. 6/18/2023 Vickie 15
  • 16. General Properties of MHC Molecules The polymorphic amino acid residues of MHC molecules are located in and adjacent to the peptide-binding cleft.  This cleft is formed by the folding of the amino termini of the MHC-encoded proteins and is composed of paired α helices forming the two walls of the cleft, resting on a floor made up of an eight-stranded β-pleated sheet.  This portion of the MHC molecule binds peptides for display to T cells, and the antigen receptors of T cells interact with the displayed peptide and also with the α helices of the MHC molecules. 6/18/2023 Vickie 16
  • 17. General Properties of MHC Molecules  The nonpolymorphic Ig-like domains of class II and class I MHC molecules contain binding sites for the T cell molecules CD4 and CD8, respectively.  CD4 and CD8 are expressed on distinct subpopulations of mature T lymphocytes and participate, together with antigen receptors, in the recognition of antigen.  CD4 binds selectively to class II MHC molecules, and CD8 binds to class I molecules.  This is why CD4+ helper T cells recognize class II MHC molecules displaying peptides, whereas CD8+ T cells recognize class I MHC molecules with bound peptides.. 6/18/2023 Vickie 17
  • 18. Class I MHC Molecules • Class I MHC molecules consist of two noncovalently linked polypeptide chains, an MHC- encoded α chain (or heavy chain) and a non-MHC– encoded subunit called β2- macroglobulin. • The amino-terminal α1 and α2 segments of the α chain interact to form a platform of an eight- stranded, antiparallel β-pleated sheet supporting two parallel strands of α helix. 6/18/2023 Vickie 18
  • 19. Class I MHC Molecules • This forms the peptide-binding cleft of class I molecules. Its size is large enough to bind peptides of 8 to 11 amino acids in a flexible, extended conformation. • The α3 segment of the α chain folds into an Ig domain whose amino acid sequence is conserved among all class I MHC molecules. • This segment contains most of the binding site for CD8, but β2-microglobulin and a small part of the nonpolymorphic C-terminal portion of the α2 domain also contribute. 6/18/2023 Vickie 19
  • 20. Class I MHC Molecules • The fully assembled class I molecule is a trimeric complex consisting of an α chain, β2-microglobulin, and a bound peptide, and stable expression of class I molecules on cell surfaces requires the presence of all three components of the complex. • Most individuals are heterozygous for MHC genes and therefore express six different class I molecules on every cell, containing α chains encoded by the two inherited alleles of HLA-A, B, and C genes. 6/18/2023 Vickie 20
  • 21. Class II MHC Molecules • Class II MHC molecules are composed of two noncovalently associated polypeptide chains, a 32- to 34-kD α chain, and a 29- to 32-kD β chain. • Unlike class I molecules, the genes encoding both chains of class II molecules are polymorphic and located in the MHC locus. • The amino-terminal α1 and β1 segments of the class II chains interact to form the peptide-binding cleft, which is structurally similar to the cleft of class I molecules. 6/18/2023 Vickie 21
  • 22. Class II MHC Molecules • The ends of the peptide-binding cleft of class II MHC molecules are open, so peptides of 30 residues or more can bind. • The α2 and β2 segments of class II MHC molecules, like class I α3 and β2-microglobulin, are folded into Ig domains and are nonpolymorphic—that is, they do not vary among alleles of a particular class II gene. • Both the α2 and β2 domains of class II molecules contribute to a concavity that accommodates a protrusion of the CD4 protein, thus allowing binding to occur. 6/18/2023 Vickie 22
  • 23. Class II MHC Molecules • The fully assembled class II MHC molecule is a trimer consisting of one α chain, one β chain, and a bound antigenic peptide, and stable expression of class II molecules on cell surfaces requires the presence of all three components of the complex. • Humans inherit, from each parent, one DPA and one DPB gene encoding, respectively, the α and β chains of an HLA-DP molecule; one functional DQA and one DQB gene; one DRA and one or two functional DRB genes. • Thus, each heterozygous individual expresses six to eight pairs of class II MHC α and β chain molecules, one set each of DP and DQ, and one or two of DR. 6/18/2023 Vickie 23
  • 24. Features of Class I and Class II MHC Molecules 6/18/2023 Vickie 24
  • 25. Features of Class I and Class II MHC Molecules Cont….. 6/18/2023 Vickie 25
  • 26. Binding of Peptides To MHC  Characteristics of Peptide-MHC Molecule Interactions • MHC molecules show a broad specificity for peptide binding, in contrast to the fine specificity of antigen recognition by the antigen receptors of lymphocytes. • In other words, a single MHC allele (e.g., HLA-A2) can present any one of many different peptides to T cells, but a single T cell will recognize only one of these many possible HLA-A2/peptide complexes. • There are several important features of the interactions of MHC molecules and antigenic peptides. 6/18/2023 Vickie 26
  • 27. Binding of Peptides To MHC 6/18/2023 Vickie 27
  • 29. Binding of Peptides To MHC Each class I or class II MHC molecule has a single peptide-binding cleft that binds one peptide at a time, but each MHC molecule can bind many different peptides. It is not surprising that a single MHC molecule can bind multiple peptides, because each individual contains only a few different MHC molecules and these must be able to present peptides from the enormous number of protein antigens that one is likely to encounter. 6/18/2023 Vickie 29
  • 30. Binding of Peptides To MHC The peptides that bind to MHC molecules share structural features that promote this interaction.  One of these features is the size of the peptide—class I molecules can accommodate peptides that are 8 to 11 residues long, and class II molecules bind peptides that may be 10 to 30 residues long or longer, the optimal length being 12 to 16 residues.  In addition, peptides that bind to a particular MHC molecule contain amino acid residues that allow complementary interactions between the peptide and that MHC molecule.  The residues of a peptide that bind to MHC molecules are distinct from those that are recognized by T cells. 6/18/2023 Vickie 30
  • 31. Binding of Peptides To MHC MHC molecules acquire their peptide cargo during their biosynthesis and assembly inside cells. Therefore, MHC molecules display peptides derived from microbial antigens that are inside host cells, and this is why MHC-restricted T cells are able to recognize microbes that infect or are ingested into cells. Importantly, class I MHC molecules acquire peptides from cytosolic proteins that are digested into peptides by a cytosolic enzyme complex, and class II molecules acquire peptides from extracellular proteins that are ingested into and digested in endocytic vesicles. 6/18/2023 Vickie 31
  • 32. Binding of Peptides To MHC The association of peptides and MHC molecules is a saturable interaction with a very slow off-rate.  In a cell, several chaperones and enzymes facilitate the binding of peptides to MHC molecules.  Once formed, most peptide-MHC complexes are stable, and kinetic dissociation constants are indicative of long half-lives that range from hours to many days.  This extraordinarily slow off-rate of peptide dissociation from MHC molecules ensures that after an MHC molecule has acquired a peptide, it will display the peptide long enough to maximize the chance that a particular T cell will find the peptide it can recognize and initiate a response. 6/18/2023 Vickie 32
  • 33. Binding of Peptides To MHC  Very small numbers of peptide-MHC complexes are capable of activating specific T lymphocytes.  Because APCs continuously present peptides derived from all the proteins they encounter, only a very small fraction of cell surface peptide–MHC complexes will contain the same peptide.  It has been estimated that as few as 100 complexes of a particular peptide with a class II MHC molecule on the surface of an APC can initiate a specific T cell response.  This represents less than 0.1% of the total number of class II molecules likely to be present on the surface of the APC. 6/18/2023 Vickie 33
  • 34. Binding of Peptides To MHC The MHC molecules of an individual can bind and display foreign peptides (e.g., those derived from microbial proteins) as well as peptides derived from the proteins of that individual (self antigens)  In fact, most of the peptides being displayed normally by APCs are derived from self proteins.  Self peptide–MHC complexes do not induce autoimmunity because T cells specific for such complexes are killed or inactivated.  In fact, T cells with receptors for self antigens must recognize self peptides displayed by self MHC molecules in order to be eliminated or made unresponsive. These processes ensure that T cells are normally tolerant to self antigens. 6/18/2023 Vickie 34
  • 35. The Phenomenon Of MHC Restriction The formal proof that the MHC is involved in antigen recognition by T cells came from the experimental demonstration of MHC restriction by Rolf Zinkernagel and Peter Doherty. Thus, T cells must be specific not only for the antigen but also for MHC molecules, and T cell antigen recognition is restricted by the MHC molecules a T cell sees. Subsequent studies established that the recognition of antigens by CD8+ CTLs is restricted by class I MHC molecules, and the responses of CD4+ helper T lymphocytes to antigens are restricted by class II MHC molecules. 6/18/2023 Vickie 35
  • 36. The Phenomenon Of MHC Restriction 6/18/2023 Vickie 36
  • 37. T-cell Receptors • Protein complex found on the surface of T Lymphocytes that is responsible for recognizing fragments of antigens as peptides bound to major histocompatibility complex molecules. • The practical function of these receptors is to enable a T‐cell to probe the surfaces of cells looking for nonself peptides.  If a T‐cell finds a peptide–MHC combination that is a good match for its TCR it will become activated, undergo clonal expansion, and differentiate to a mature effector T‐cell capable of joining the fight against the infectious agent generating these nonself peptides. 6/18/2023 Vickie 37
  • 38. T-cell Receptors Structure:  The antigen receptor is a heterodimer consisting of two transmembrane polypeptide chains, designated TCR α and β, covalently linked to each other by a disulfide bridge between extracellular cysteine residues.  Each TCR α and β chain consists of one Ig-like N-terminal variable (V) domain, one Ig-like constant (C) domain, a hydrophobic transmembrane region, and a short cytoplasmic region.  Thus, the extracellular portion of the TCR αβ heterodimer is structurally similar to the antigen-binding fragment (Fab) of an Ig molecule, which is made up of the V and C regions of a light chain and the V region and the first C region of a heavy chain. 6/18/2023 Vickie 38
  • 39. T-cell Receptors 6/18/2023 Vickie 39 Structure of the T-cell Receptor:
  • 40. T-cell Epitopes • T-cell epitopes are peptides derived from antigens and recognized by the TCR when bound to MHC molecules displayed on the cell surface of APCs. • CD4 T-cells express the CD4 coreceptor, which binds to MHC II, and recognize peptides presented by MHC II molecules. • CD8 T-cells express the CD8 coreceptor, which binds to MHC I, and recognize peptides presented by MHC I molecules. • T cell epitopes presented by MHC class I molecules are typically peptides between 8 and 11 amino acids in length whereas MHC class II molecules present 13-17 a.acids. 6/18/2023 Vickie 40
  • 41. Function of T cell receptor What Does the αβ T Cell Receptor (TCR) Recognize? • Only fragments of proteins (peptides) associated with MHC molecules on surface of cells • Helper T cells (Th) recognize peptide associated with MHC class II molecules • Cytotoxic T cells (Tc) recognize peptide associated with MHC class I molecules 6/18/2023 Vickie 41
  • 43. T-cell Markers • Is a group of cell surface protein marker on the white blood cells used to classify immune cell types and establish international nomenclature standards. • The markers are found on many blood cells and are most often used to refer Lymphocytes, • The system of assigning markers is intended for classification of many monoclonal antibodies generated by different laboratories around the world against epitopes on the surface molecules of leukocytes. 6/18/2023 Vickie 43
  • 44. T-cell Markers Designation/Nomenclature These cell surface markers are designated by prefix CD followed by a number. The number reflect the order in which the cell surface marker was discovered. At present it ranges from CD1 to CD371. It is useful in identifying many different types of Leukocytes. It tells about cell lineage, species to which cell belong, stage of maturation or activation of the cell. 6/18/2023 Vickie 44
  • 45. B-cell Epitopes • Antigen-antibody interaction is a key event in humoral immune response to invading pathogen. • A specific antibody (Ab) recognizes antigen (Ag) at discrete regions known as antigenic determinants or B-cell epitopes. • B-cell epitopes can be defined as a surface accessible clusters of amino acids, which are recognized by secreted antibodies or B-cell receptors and are able to elicit cellular or humoral immune response 6/18/2023 Vickie 45
  • 46. B-cell Epitopes • B-cell epitopes are solvent-exposed portions of the antigen that bind to secreted and cell- bound Igs. • B-cell receptors encompass cell- bound Igs, consisting of two heavy chains and two light chains. • The different chains and regions are annotated. B-cell epitope 6/18/2023 Vickie 46
  • 47. B-cell Epitopes • Based on the spatial structure B-cell epitopes can be categorized as; – a continuous (linear or sequential) and – discontinuous (nonlinear or conformational) epitopes; • in the latter case amino acid residues are in close contact due to the three-dimensional conformation. • Antibodies are developed to bind the epitope with high affinity by using complementary determining regions (CDRs). 6/18/2023 Vickie 47
  • 48. Function of B Cell What Does The B Cell Immunoglobulin (Ig) Receptor Recognize? • Proteins (conformational determinants, denatured or proteolyzed determinants) • Nucleic acids • Polysaccharides • Some lipids • Small chemicals (haptens) 6/18/2023 Vickie 48
  • 49. Toll-like Receptors • Toll-like receptors (TLRs) are an evolutionarily conserved family of pattern recognition receptors expressed on many cell types that recognize products of a wide variety of microbes, as well as molecules expressed or released by stressed and dying cells. • Named on the basis of their similarity to the Toll receptor in the fruit fly, Drosophila. • There are 10 expressed TLR genes in humans and each is devoted to recognizing a distinct set of molecular patterns that are not found in healthy vertebrate cells. 6/18/2023 Vickie 49
  • 50. Toll-like Receptors Structure  All TLRs have the same basic structural features, with multiple N‐terminal leucine‐rich repeats (LRRs) arranged in a horseshoe‐ or crescent‐shaped solenoid structure that acts as the PAMP‐binding domain.  All mammalian TLR proteins have a TIR (for Toll-IL-l receptor) domain in their cytoplasmic tail, which interacts with other TIR-type domains, usually in other signalling molecules. 6/18/2023 Vickie 50
  • 52. Toll-like Receptors Location  TLRs are found on the cell surface and on intracellular membranes and are thus able to recognize microbes in different cellular locations.  TLRs 1, 2, 4, 5, and 6 are expressed on the plasma membrane, where they recognize various PAMPs in the extracellular environment.  In contrast, TLRs 3, 7, 8, and 9 are mainly expressed inside cells on endoplasmic reticulum and endosomal membranes, where they detect several different microbial nucleic acids. 6/18/2023 Vickie 52
  • 53. Toll-like Receptors Location The cellular locations of the mammalian Toll-like receptors 6/18/2023 Vickie 53
  • 54. Toll-like Receptors Ligands  Mammalian TLRs are involved in responses to a wide variety of molecules that are expressed by microbes but not by healthy mammalian cells.  The ligands that the different TLRs recognize are structurally diverse and include products of all classes of microorganisms. – Examples of bacterial products that bind to TLRs are the bacterial cell wall constituents (LPS and lipoteichoic acid), flagellin, a protein subunit component of the flagella of motile bacteria. – Examples of nucleic acids that are TLR ligands are double- stranded RNAs, single-stranded RNAs, and unmethylated CpG dinucleotides 6/18/2023 Vickie 54
  • 56. Toll-like Receptors • Upon binding of a PAMP, TLRs transduce signals into the cell via their TIR domains, which recruit adaptor proteins within the cytoplasm that possess similar TIR motifs. • These adaptors propagate the signal downstream, culminating in activation of NFκB and interferon regulatory family (IRF) transcription factors (AP-1, IRF3, and IRF7). • NF-κB and AP-1 stimulate the expression of genes encoding many of the molecules required for inflammatory responses, including inflammatory cytokines (TNF and IL-1), chemokines (CCL2 and CXCL8), and endothelial adhesion molecules ( E- selectin). 6/18/2023 Vickie 56
  • 57. Toll-like Receptors • IRF3 and IRF7 promote production of type I interferons (IFN-α and IFN-β), which are important for antiviral innate immune responses. • Different combinations of adaptors and signaling intermediates are used by different TLRs, accounting for the common and unique downstream effects of the TLRs. • For example, cell surface TLRs that engage the adaptor MyD88 lead to NF-κB activation, and TLR signaling that uses the adaptor called TRIF (TIR domain– containing adaptor inducing IFN-β) leads to IRF3 activation. 6/18/2023 Vickie 57
  • 59. REFERENCES 1. Delves, P., Martin, S., Burton, D. and Roitt, I., 2017. Roitt's essential immunology. 13th ed. Oxford: WILEY Blackwell, pp.23-24. 2. Potocnakova, L., Bhide, M., & Pulzova, L. B. (2016). An Introduction to B- Cell Epitope Mapping and In Silico Epitope Prediction. Journal of immunology research, 2016, 6760830. https://doi.org/10.1155/2016/6760830 3. Abbas, A., Lichtman, A. and Pillai, S., 2018. Cellular and molecular immunology. 9th ed. Philadelphia: ELSEVIER. 4. Kenneth, M., Weaver, C. and Janeway, C., 2017. Janeway's immunobiology. 9th ed. New York: Garland Science. 5. Handbook of Systemic Autoimmune Diseases, 2017 6/18/2023 Vickie 59

Notes de l'éditeur

  1. PRRs=Pattern recognition receptors NOD=Nucleotide oligomerization domain (NOD) This recognition is carried out by a series of recognition molecules or receptors. Some of these circulate freely in blood or body fluids, others are fixed to the membranes of various cells or reside inside the cell cytoplasm. In every case, some constituent of the foreign material must interact with the recognition molecule like a key fitting into the right lock. This initial act of recognition opens the door that leads eventually to a full immune response. These receptors are quite different in the innate and the adaptive immune system. The innate system possesses a limited number, known as pattern-recognition receptors (PRRs), which have been selected during evolution to recognize structures common to groups of disease causing organisms such as the lipopolysaccharide (LPS) in some bacterial cell walls. These PRRs act as the ‘early warning' system of immunity, triggering a rapid inflammatory response which precedes and is essential for a subsequent adaptive response. In contrast, the adaptive system has thousands of millions of different receptors on its B and T lymphocytes, each one exquisitely sensitive to one individual molecular structure. The responses triggered by these receptors offer more effective protection against infection, but are usually much slower to develop. Linking the two systems are the families of major histocompatibility complex (MHC) molecules, specialized for ‘serving up' foreign molecules to T lymphocytes. Another set of ‘linking' receptors are those by which molecules such as antibody and complement become bound to cells, where they can themselves act as receptors.
  2. Toll-like receptors (TLRs) recognize endogenous and exogenous danger signals, consist of an extracellular domain containing leucine-rich repeats (LRRs) for ligand binding and a cytoplasmic Toll/IL-1 receptor domain that links to adapter proteins and complex signaling pathways. Nucleotide oligomerization domain (NOD)-like receptors are a family of 22 proteins that contain LRRs for potential ligand binding, a NOD, and a caspase activation and recruitment domain (CARD), Pyrin domain, or a baculovirus inhibitor of apoptosis repeat (BIR) domain for initiation of signaling. Retinoic acid-inducible gene (RIG)-like receptors consist of two N-terminal CARDs for signaling and an RNA helicase domain C-type lectin receptors (CLRs) contain a C (Ca++)-type recognition domain and mediate diverse functions, depending upon the signaling pathways they activate Scavenger receptors (SRs) are a diverse group of receptors that recognize a variety of ligands, mediate uptake of oxidized lipoproteins, and may be involved in atherosclerotic plaque formation.
  3. α-chains of the MHC class I molecules (HLA)-A, HLA-B, and HLA-C and the α- and β-chains of the MHC class II molecules HLA-DR, HLA-DP, and HLA-DQ, all of which are expressed in a co-dominant fashion.
  4. α-chains of the MHC class I molecules (HLA)-A, HLA-B, and HLA-C and the α- and β-chains of the MHC class II molecules HLA-DR, HLA-DP, and HLA-DQ, all of which are expressed in a co-dominant fashion.
  5. This pattern of MHC expression is linked to the functions of class I–restricted CD8+ and class II–restricted CD4+ T cells. Thus, the expression of class I MHC molecules on nucleated cells provides a display system for viral and tumor antigens, so these antigens can be recognized by CTLs and the antigen-producing cells can be killed.
  6. Thus, innate immune responses to viruses increase the expression of the MHC molecules that display viral antigens to virus specific T cells. This is one of the mechanisms by which innate immunity stimulates adaptive immune responses IFN-γ may be produced by natural killer (NK) cells during early innate immune reactions and by antigen activated T cells during later adaptive immune reactions. Thus, IFN-γ also provides a mechanism by which innate immunity promotes adaptive immunity, by increasing class II MHC expression on APCs, and provides an amplification mechanism in adaptive immunity. the expression of class II molecules increases in response to signals from Toll-like receptors responding to microbial components, thus promoting the display of microbial antigens—another link between innate and adaptive immunity.
  7. By keeping the complex of transcription factors together, CIITA functions as a master regulator of class II gene expression. Mutations in CIITA or the associated transcription factors have been identified as the cause of human immunodeficiency diseases associated with defective expression of MHC molecules. The best studied of these disorders is bare lymphocyte syndrome. The expression of many of the proteins involved in antigen processing and presentation is coordinately regulated. For instance, IFN-γ increases the transcription not only of class I and class II genes but also of several genes whose products are required for class I MHC assembly and peptide display, such as genes encoding the TAP transporter and some of the subunits of proteasomes, discussed later in this chapter.
  8. All MHC molecules share certain structural characteristics that are critical for their role in peptide display and antigen recognition by T lymphocytes.
  9. The polymorphic residues, which are the amino acids that vary among different MHC alleles, are located in the floor and walls of this cleft. Because of amino acid variability in this region, different MHC molecules bind and display different peptides and are recognized by the antigen receptors of different T cells. This schematic illustration shows an MHC molecule binding and displaying a peptide and a T cell receptor recognizing the complex of peptide and MHC molecule. As discussed later in the text, MHC-associated peptides contain some residues that anchor them into pockets in the cleft of the MHC molecule and other residues that are recognized by T cell antigen receptors. MHC residues that may vary among individuals (polymorphic residues) are also recognized by the T cell receptor. Thus, T cells see both peptide antigens and MHC molecules.
  10. For this reason, CD4 and CD8 are called T cell coreceptors. Stated differently, CD4+ T cells are class II MHC restricted and CD8+ T cells are class I MHC restricted
  11. The polymorphic residues of class I molecules are confined to the α1 and α2 domains, where they contribute to variations among different class I alleles in peptide binding and T cell recognition.
  12. The polymorphic residues of class I molecules are confined to the α1 and α2 domains, where they contribute to variations among different class I alleles in peptide binding and T cell recognition.
  13. Four strands of the floor of the cleft and one of the α-helical walls are formed by the α1 segment, and the other four strands of the floor and the second wall are formed by the β1 segment. The polymorphic residues are located in the α1 and β1 segments, in and around the peptide binding cleft, as in class I MHC molecules. In human class II molecules, most of the polymorphism is in the β chain.
  14. Typically, there is not much pairing of MHC proteins from different loci (i.e., DRα with DQβ, and so on), and each haplotype tends to be inherited as a single unit. However, because some haplotypes contain extra DRB loci that produce β chains that assemble with DRα, and some DQα molecules encoded on one chromosome can associate with DQβ molecules produced from the other chromosome, the total number of expressed class II molecules on the cells of some individuals may be more than eight.
  15. Peptide binding to MHC molecules. A, These top views of the crystal structures of MHC molecules show how peptides lie in the peptide-binding clefts. The class I molecule shown is HLA-A2, and the class II molecule is HLA-DR1. The cleft of the class I molecule is closed, whereas that of the class II molecule is open. As a result, class II molecules accommodate longer peptides than class I molecules. B, The side view of a cutout of a peptide bound to a class II MHC molecule shows how anchor residues of the peptide hold it in the pockets in the cleft of the MHC molecule.
  16. It is not surprising that a single MHC molecule can bind multiple peptides, because each individual contains only a few different MHC molecules (6 class I and about 8 or more class II molecules in a heterozygous individual),
  17. The inability of MHC molecules to discriminate between self and foreign peptides raises the question, Why do we normally not develop immune responses against self proteins?
  18. In their classic study, reported in 1974, these investigators examined the recognition of virus-infected cells by virus-specific CTLs in inbred mice. If a mouse is infected with a virus, CD8+ T cells specific for the virus are activated and differentiate into CTLs in the animal. When the function of these CTLs is analyzed in vitro, they recognize and kill virus-infected cells only if the infected cells express MHC molecules that are expressed in the animal from which the CTLs were removed
  19. Experimental demonstration of the phenomenon of MHC restriction of T lymphocytes. Virus-specific CTLs generated from virus-infected strain A mice kill only syngeneic (strain A) target cells infected with that virus. The CTLs do not kill infected strain B targets (which express different MHC alleles than does strain A). By use of congenic mouse strains that differ only at class I MHC loci, it has been proved that recognition of antigen by CD8+ CTLs is self class I MHC restricted.
  20. The schematic diagram of the αβ TCR (left) shows the domains of a typical TCR specific for a peptide-MHC complex. The antigen-binding portion of the TCR is formed by the Vβ and Vα domains. The ribbon diagram (right) shows the structure of the extracellular portion of a TCR as revealed by x-ray crystallography. The hypervariable segment loops that form the peptide- MHC binding site are at the top.
  21. TCR Recognizes its Epitope Only in the Context of MHC CD4 TCR – peptide/MHC Class II CD8 TCR – peptide/MHC Class I
  22. Since then, its use has expanded to many other cell types, and more than 370 CD unique clusters and subclusters have been identified.
  23. Toll‐like receptor (TLR) structure. Ribbon diagram. Leucine‐rich repeats (LRRs) are colored from blue to red, beginning at LRR1 and proceeding to LRR23, as indicated. NT, N‐terminus; CT, C‐terminus.
  24. Some TLRs are located on the cell surface of dendritic cells, macrophages, and other cells, where they are able to detect extracellular pathogen molecules. TLRs are thought to act as dimers; only those that form heterodimers are shown in dimeric form here. The rest act as homodimers. TLRs located intracellularly, in the walls of endosomes, can recognize microbial components, such as DNA, that are accessible only after the microbe has been broken down. The diacyl and triacyl lipopeptides recognized by the heterodimeric receptors TLR-6:TLR-2 and TLR-1 :TLR-2, respectively, are derived from the lipoteichoic acid of Gram-positive bacterial cell walls and the lipoproteins of Gram-negative bacterial surfaces.
  25. activation protein 1 (AP-1), interferon response factor 3 (IRF3), and IRF7 which regulate the transcription of a whole battery of inflammatory cytokines and chemokines
  26. Ligand induced TLR dimerization is predicted to bring the TIR domains of the cytoplasmic tails of each protein close to one another
  27. All TLRs except TLR3 signal through MyD88 and are therefore capable of activating NF-κB and inducing an inflammatory response. TLR3 signals through TRIF and therefore activates IRF3, which stimulates production of type I interferons. TLR4 signals through both MyD88 and TRIF and is able to induce both types of responses. The endosomal TLRs 7 and 9, which are most highly expressed in plasmacytoid DCs signal through a MyD88-dependent, TRIF-independent pathway that activates both NF-κB and IRFs. Therefore, TLR7 and TLR9, like TLR4, induce both inflammatory and antiviral responses.