2. IMPORTANT
POINTS
• What is Adaptive Immune Response?
• What is the difference between T and B cell function
for adaptive immune response?
• What are Antigen-Presenting Cells (APCs)?
• What is the role of MHC in adaptive response?
Monday, July 9, 2012
3. ADAPTIVE IMMUNE
RESPONSE
• initiated when antigen receptors of lymphocytes recognize the antigens
• B lymphocytes receptors (membrane-bound-antibodies): proteins,
polysaccharides, lipids, nucleic acids, small chemicals in soluble or cell surface-
associated form
• humoral
• generated against many types of microbial cell walls and soluble antigens
• T lymphocytes receptors: peptide fragments of protein antigens
• presented by specialized display molecules on host cells
• cell-mediated
• generated only against the protein antigens of microbes that are
associated with host cells
Monday, July 9, 2012
4. BARRIERS TO THE
INDUCTION OF ADAPTIVE
IMMUNE RESPONSE
• low frequency of naive lymphocytes in the body
specific for any one antigen (may be less than 1 in
every 100,000) which has to LOCATE and REACT
rapidly to the antigen wherever it is introduced
• different kinds of microbes need to be combated by
different types of adaptive response (even to the same
microbe at different stages of its life)
• e.g. virus (blood stages = antibodies; host cell
stages = CTLs)
Monday, July 9, 2012
5. ANTIGEN
CAPTURE &
PRESENTATION
Monday, July 9, 2012
6. ANTIGEN RECOGNITION
BY T LYMPHOCYTES
• The majority of T lymphocytes recognize
peptide antigens that are bound to and displayed
by the major histocompatibility complex (MHC)
molecules of antigen-presenting cells (APCs).
• MHC: genetic locus whose principal products
function as the peptide display molecules of the
immune system
• MHC restriction: unique for each individual;
different clones of T cells can see peptides only
when these peptides are displayed by that
individual's MHC molecules
Monday, July 9, 2012
7. ANTIGEN RECOGNITION
BY T LYMPHOCYTES
• DUAL SPECIFICITY
OF T-CELLS:
• T cell receptor (TCR)
recognizes some
residues of peptide
antigen
• T cell receptor (TCR)
recognizes residues
of the MHC molecule
that is displaying
that peptide
Monday, July 9, 2012
8. ANTIGEN-PRESENTING
CELLS (APCs)
• specialized cells that capture microbial antigens and display
them for recognition by T lymphocytes
• “professional” APCs: ability to both display antigens for T
cells and provide the additional signals needed to activate
naive T cells
• Differentiated effector T cells again need to see antigens
presented by various APCs, to activate the effector
functions of the T cells in humoral and cell-mediated
immune responses.
• How does APCs present antigens to trigger immune
responses?
• What is the role of MHC molecules in these processes?
Monday, July 9, 2012
9. CAPTURE OF PROTEIN
ANTIGENS BY APCs
• Protein antigens of microbes
that enter the body are
captured by professional APCs
and are concentrated in the
peripheral lymphoid organs
where immune are initiated
Monday, July 9, 2012
10. CAPTURE OF PROTEIN
ANTIGENS BY APCs
• Epithelia contain a
population of
professional APCs
that belong to the
lineage of dendritic
cells
• The same cells are
present in the T-cell
rich areas of
peripheral lymphoid
organs, and in smaller
number, in most
other organs
Monday, July 9, 2012
11. CAPTURE OF PROTEIN
ANTIGENS BY APCs
• Langerhans cells: epidermal dendritic cells
in the skin
• “immature” = inefficient in stimulating T-
lymphocytes
• capture the antigens:
• phagocytosis = for particulate antigens
• pinocytosis = soluble antigens
Monday, July 9, 2012
13. CAPTURE OF PROTEIN
ANTIGENS BY APCs
• During their migration, and probably in response to
the microbe the dendritic cells mature; and in the
lymph nodes, the dendritic cells present antigens to
naive T-lymphocytes
• Dendritic cells at different stages of their
maturation may express different membrane
proteins
• Immature dendritic cells express surface receptors
that capture microbial antigens, whereas mature
dendritic cells express high levels of MHC molecules
and co-stimulators, which function to stimulate T-
cells
Monday, July 9, 2012
14. CAPTURE OF PROTEIN
ANTIGENS BY APCs
• Different types of APCs serve distinct functions in T-cell dependent
immune response
• Dendritic cells: principal inducers of such responses because
dendritic cells are the most potent APCs for activating naive T-
lymphocytes; Dendritic cells not only initiate T-cell responses
but may also influence the nature of the response
• Macrophages: phagocytose microbes and display the antigens of
these microbes to effector T-cells, which activate the
macrophage to kill the microbes
• B-lymphocytes: ingest protein antigens and display them to
helper T cells; this process is important for the development of
humoral immune responses
• NOTE: all nucleated cells can present antigens derived from microbes in
the cytoplasm to CTLs
Monday, July 9, 2012
15. CAPTURE OF PROTEIN
ANTIGENS BY APCs
• Professional APCs may also be involved in initiating the responses of
CD8+ T-lymphocytes to the antigens of intracellular microbes
• CROSS-PRESENTATION (or cross-priming):
• one cell-type, the professional APCs, can present the antigens of other
cells, the infected cells, and prime (or activate) naive T lymphocytes
specific for these antigens
• The professional APCs that ingest infected cells may also present the
microbial antigens toCD4+ helper T-lymphocytes. Thus, both classes of
T lymphocytes, CD4+ and CD8+ cells, specific for the same microbe are
activated close to one another
• IMPORTANCE: for the antigen-stimulated differentiation of naive CD8+
T cells to effector CTLs which often requires help from CD4+ T-cells.
Once the CD8+ T cells have differentiated into CTLs, they kill infected
host cells without any need for professional APCs or signals other than
recognition of antigen
Monday, July 9, 2012
19. MAJOR
HISTOCOMPATIBILITY
COMPLEX (MHC)
• membrane proteins on APCs that display peptide
antigens for recognition by T lymphocytes
• discovered as the genetic locus that is the principal
determinant of acceptance or rejection of tissue grafts
exchanged between individuals
• individuals that are identical at their MHC locus (inbred
animals and identical twins) will accept grafts from one
another, and individuals that differ at their MHC loci
will reject such grafts
• physiologic function: to display peptides derived from
protein antigens to antigen-specific T-lymphocyte
Monday, July 9, 2012
20. MAJOR
HISTOCOMPATIBILITY
COMPLEX (MHC)
• MHC locus is a collection of genes found in all mammals
• Human MHC proteins are called human leukocyte antigens
(HLA),
because these
proteins
were discovered as antigens
of leukocytes that could be identified with specific
antibodies; the genes encoding these molecules make up
the HLA locus
• In all species, the MHC locus contains two sets of highly
polymorphic genes, called the class 1 and class II MHC
genes
• These genes encode the class I and class II MHC molecules
that display peptides to T-cells
Monday, July 9, 2012
21. MAJOR
HISTOCOMPATIBILITY
COMPLEX (MHC)
Monday, July 9, 2012
22. CLASS I & CLASS II MHC MOLECULES ARE
MEMBRANE PROTEINS THAT EACH
CONTAINS A PEPTIDE-BINDING CLEFT AT
ITS AMINO TERMINAL END
Monday, July 9, 2012
23. CLASS I & CLASS II MHC MOLECULES ARE
MEMBRANE PROTEINS THAT EACH
CONTAINS A PEPTIDE-BINDING CLEFT AT
ITS AMINO TERMINAL END
Monday, July 9, 2012
25. PROPERTIES OF MHC
GENES & MOLECULES
• Class I molecules are expressed on all nucleated cells, but
Class II molecules are expressed mainly on professional
APCS such as dendritic cells, and on macrophages and B
lymphocytes
Monday, July 9, 2012
26. PROPERTIES OF MHC
GENES & MOLECULES
• The peptide-binding clefts of
MHC molecules bind peptides
derived from protein antigens
and display these peptides for
recognition by T cells
Monday, July 9, 2012
38. IMPORTANT
POINTS
• How do the antigen receptors of lymphocytes
recognize extremely diverse antigens and transmit
quite conserved activating signals to the cells?
• How is the vast diversity of receptor structures
generated in lymphocytes?
• NOTE: The diversity of antigen recognition implies the
existence of many structurally different antigen
receptor proteins, more than can be reasonably
encoded in the inherited genome (germline) = THUS,
there must be special mechanisms for generating this
diversity!
Monday, July 9, 2012
