Chapter 5 Immunology

Chapter 5 Antigen Recognition by T Lymphocytes

Chapter 5 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

B lymphocytes versus T lymphocytes: Similarities ,[object Object],[object Object],[object Object],[object Object],[object Object]

Fab Domain structure of TCR is similar to Ig

B lymphocytes versus T lymphocytes: Differences ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Key Difference between Ig and TCR antigen recognition ,[object Object]

Major histocompatibility complex (MHC) ,[object Object],[object Object],[object Object],[object Object],[object Object]

T-cell receptor ,[object Object],[object Object],[object Object],[object Object],[object Object]

T-cell development ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

The T-cell receptor resembles a membrane associated Fab fragment of Ig ,[object Object],[object Object],[object Object],[object Object],[object Object]

Organization of TCR  and  chains ,[object Object],[object Object],[object Object],[object Object]

Comparison of a.a. sequences of V domains from different clones of T-cells ,[object Object],[object Object],[object Object]

T-cell receptor binding ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

T-cell receptor diversity is generated by gene rearrangement ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

T-cell receptor is used only for the recognition of Ag ,[object Object],[object Object],[object Object]

Human TCR  chain locus (Chr 14) Human TCR  -chain locus (Chr 7) ,[object Object],[object Object],[object Object],[object Object],[object Object]

TCR rearrangement occurs during T cell development in the thymus ,[object Object],[object Object],[object Object],[object Object],[object Object]

Rare genetic defect in a RAG gene = Severe combined immunodeficiency disease (SCID) ,[object Object],[object Object],[object Object],Candida albicans infection

Missense mutations that produce RAG proteins with partial enzymatic activity = Omenn syndrome ,[object Object],[object Object],Red rash on face and shoulders

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Expression of the TCR on the cell surface requires association with additional proteins ,[object Object],[object Object],[object Object],[object Object]

Expression of the TCR on the cell surface requires association with additional proteins (cont.) ,[object Object],[object Object]

TCR complex ,[object Object],[object Object],[object Object]

 And  chains form a second class of TCR expressed by a distinct population of T-cells =  :  TCR ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

The germline organization of the  and  loci resembles that of the  and  loci ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

[object Object],[object Object]

Rearrangement at the  and  loci resembles that of the  and  loci ,[object Object],[object Object],[object Object],[object Object]

Antigen processing and presentation

B cells can recognize a wide range of molecules in their native form.

TCR recognize Ag as a peptide bound to MHC on human cell surface ,[object Object]

Microorganisms that infect the human body can be broadly divided into two intracellular and extracellular ,[object Object],[object Object],[object Object],[object Object],[object Object]

Two class of T cells are specialized to respond to intracellular and extracellular sources of infection ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

The structures of CD4 and CD8 glycoproteins ,[object Object],Ig-like domains

CD4 T-cells are helper T-cells ,[object Object],[object Object],[object Object]

T-cells function by making contact with other cells

Two classes of MHC molecule present antigen to CD8 and CD4 T-cells respectively ,[object Object],[object Object],[object Object],[object Object],[object Object]

The two classes of MHC membrane glycoprotein molecules have similar 3-D structures ,[object Object],[object Object],[object Object],[object Object]

[object Object],[object Object],[object Object],The two classes of MHC membrane glycoprotein molecules have similar 3-D structures

The similar 3-D structures of MHC I and MHC II molecules consist of two pairs of extracellular domains ,[object Object],[object Object],[object Object],[object Object],[object Object]

MHC class I binds CD8 and MHC class II binds CD4

MHC bind a variety of peptides ,[object Object],[object Object],[object Object]

MHC I molecule binding ,[object Object],[object Object],[object Object],[object Object]

MHC II molecule binding ,[object Object],[object Object],[object Object],[object Object],[object Object]

There are 2 major compartments within cells, separated by membranes ,[object Object],[object Object],[object Object],[object Object],[object Object]

There are 2 major compartments within cells, separated by membranes ,[object Object],[object Object],[object Object],[object Object],[object Object],(2) Vesicular system (ER, Golgi, vesicles) is contiguous with extracellular fluid (1) Cytosol is contiguous with the nucleus through nuclear pores. Extracellular fluid

Peptides Generated in Cytosol are Transported into the ER where they bind MHC class I molecules ,[object Object],[object Object],[object Object],[object Object]

Peptides presented by MHC class II molecules are generated in acidified intracellular vesicles ,[object Object],[object Object],[object Object],[object Object]

The processing pathway determines which class of MHC molecule interacts with a peptide that originates from extracellular or intracellular pathogen. Intracellular pathogen Extracellular pathogen

Viral infection of human cells ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Formation and transport of peptides that bind to MHC class I molecules ,[object Object],[object Object],Tap-2 Tap-1

Formation and transport of peptides that bind to MHC class I molecules ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Tap-1 Tap-2

Newly synthesized MHC class I molecules ,[object Object],[object Object],[object Object],[object Object],[object Object]

When MHC class I heavy chains enter the ER they bind a membrane protein-calnexin ,[object Object],[object Object],[object Object],[object Object]

MHC class I H-chain binds  2-microglobulin and calnexin is released from the  :  -microglobulin ,[object Object],[object Object],[object Object]

Chaperone proteins aid the assembly and peptide loading of MHC class I molecules in the endoplasmic reticulum Golgi stacks  cell membrane

Bare lymphocyte syndrome ,[object Object],[object Object],[object Object],[object Object]

Peptides Presented by MHC Class II are Generated in Acidified Vesicles ,[object Object]

Peptides Presented by MHC Class II are Generated in Acidified Vesicles (cont.) ,[object Object],[object Object],[object Object]

Internalization of extracellular Ags by receptor-mediated endocytosis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

The pathways of the MHC class I and II

MHC Class II Molecules are Prevented from Binding Peptides in the ER by the Invariant Chain ,[object Object],[object Object],[object Object],[object Object],[object Object]

MHC class II compartments or MIIC (Endocytic vesicles ) ,[object Object],[object Object]

MHC class II compartments or MIIC (Endocytic vesicles ) ,[object Object],[object Object],[object Object]

The invariant chain prevents peptides from binding to a MHC class II molecule UNTIL…it reaches the site of extracellular protein breakdown

The TCR Specifically Recognizes Both Peptide and MHC Molecules ,[object Object],[object Object],[object Object],TCR MHC class I peptide

The TCR Specifically Recognizes Both Peptide and MHC Molecules ,[object Object],[object Object]

The TCR Specifically Recognizes Both Peptide and MHC Molecules ,[object Object],[object Object],Interact with T cell Interact with MHC

TCR-ligand:MHC molecules visualized by X-ray crystallography ,[object Object],[object Object],[object Object],TCR Ag-binding site of an Ab

Similar interactions for peptides bound to either MHC class I or class II ,[object Object],[object Object]

The CDR3 loops of the TCR  and  chains form the central part of the binding site ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

TCR does not interact symmetrically with the peptide and the helices of the MHC molecule. ,[object Object],[object Object],[object Object],[object Object],[object Object]

Most cells express MHC class I; few express MHC class II ,[object Object],[object Object]

The major histocompatibility complex

Major histocompatibility complex ,[object Object],[object Object],[object Object]

Diversity of MHC molecules in the human population is due to multigene families and genetic polymorphism ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

[object Object],[object Object],[object Object],[object Object],[object Object]

MHC class I and class II genes are linked in the MHC complex ,[object Object],[object Object],[object Object],[object Object]

In humans the MHC is called the HLA complex ,[object Object],[object Object],[object Object],6 MHC class I isotypes 5 MHC class II isotypes

Human MHC class I and II isotypes differ in function and the extent of their polymorphism ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

The polymorphism of HLA class I and class II genes ,[object Object],[object Object],[object Object],[object Object]

For each HLA class II isotype, the genes encoding the  and  chains are called A and B, respectively ,[object Object],[object Object],[object Object],[object Object]

[object Object],[object Object],[object Object],[object Object],The MHC class I and class II genes occupy different regions of the MHC on Chromosome 6

[object Object],[object Object],[object Object],The MHC class I and class II genes occupy different regions of the MHC on Chromosome 6

Other proteins involved in antigen processing an presentation are encoded in the MHC class II region ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Almost all of the genes in the HLA class II region are involved in Ag processing & presentation to T cells ,[object Object],[object Object],[object Object]

Variations between MHC allotypes is concentrated in the sites that bind peptide and T-cell Receptor ,[object Object],[object Object],[object Object]

Peptide-binding motifs and the sequence of peptides bound for some MHC isoforms ,[object Object],[object Object],[object Object]

Peptide-binding motifs and the sequence of peptides bound for some MHC isoforms ,[object Object],[object Object],[object Object],[object Object]

Polymorphism of MHC Classes I and II affects antigen recognition by T cells ,[object Object],[object Object],[object Object]

T-cell recognition of Ags is MHC restricted ,[object Object],[object Object],[object Object]

Haplotype ,[object Object],[object Object],[object Object]

MHC polymorphism is the primary cause of alloreactions that reject transplants ,[object Object],[object Object],[object Object]

Random combination of maternal and paternal haplotypes produces millions of combinations ,[object Object],[object Object],[object Object],[object Object],[object Object]

MHC heterozygosity delays the progression to AIDS in people infected with HIV-1 ,[object Object],[object Object],[object Object],Heterozygous for all HLA class I and II loci homozygous for 1 locus homozygous for 2 or 3 loci

Chapter 5 Immunology

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Chapter 5 Immunology