T Cell Receptor (TCR) & MHC Complexes-Antigen Presentation

• Pin Ling ( 凌 斌 ), Ph.D.

ext 5632; lingpin@mail.ncku.edu.tw

• References:

1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 5-7

2. Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology (7th ed., 2006), Chapter 5 & 7

QuestionQuestion

Ans: 1. VDJ gene recombination - => V regions => Ag binding 2. Somatic hypermutation -

3. Isotype switching => Fc portion => Effector function

What are the mechanisms to generate Ab diversity?

OutlineOutline• Structures & Features of T-cell antigen Structures & Features of T-cell antigen

receptor (TCR)receptor (TCR)

• Structures & Features of Major Histocompatibility Complex (MHC)

• Antigen Presentation to T cells

• Summary & Question

Antibody, TCR & MHCAntibody, TCR & MHC

Key Concepts in T-cell Receptor (TCR)

1. T-cell antigen receptor (TCR) is similar to the F(ab) of Ab but only located on the surface of T cells => No secreted form => Two major types: TCR and TCR

2. TCR functions to recognize Ag peptide and then to activate T cells => Adaptive immunity

3. Ag recognition by TCR requires Ag presented by Major Histocompatibility Complex (MHC). => consider both Ag peptide & MHC => Cell-Cell interaction

4. The Ag-binding site region of the TCR is formed by the V and V regions.

Similarities & Differences between T-cell Receptor (TCR) and Ab

The Structure of T-cell Receptor (TCR)The Structure of T-cell Receptor (TCR)

T-cell Receptor (TCR) vs. AbT-cell Receptor (TCR) vs. Ab

Binding of a TCR to a peptide-MHC cBinding of a TCR to a peptide-MHC complexomplex

Front Side

TCR & Accessory Molecules

Accessory Molecules-Help T cells in

response to a specific Ag

1. CD3 () and

chains associates w/ TCR => intracellular signaling transduction

2. CD4/CD8: CD4 MHC-II CD8 MHC-I

3. CD28: a co-stimulatory receptor

4. Integrin: Adhesion & co-stimulation

The TCR/CD3 ComplexThe TCR/CD3 ComplexTCR/CD3 Complex:

1. TCRdimer + multiple CD3

dimers - CD3dimer - CD3 dimer

- CD3 dimer

2. The ITAM motif on CD3 => Signaling

Transduction

TCR/CD3 Complex vs BCR/IgTCR/CD3 Complex vs BCR/IgComplexComplex

Interaction between innate and& adaptive immunity

1. Innate immunity => Ag presentation (by Dendritic cells)

2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

Interactions of Accessory molecules Interactions of Accessory molecules between T cells & APCsbetween T cells & APCs

OutlineOutline• Structures & Features of T-cell antigen

receptor (TCR)

• Structures & Features of Major HisStructures & Features of Major Histocompatibility Complex (MHC)tocompatibility Complex (MHC)

• Antigen presentation to T cells

• Summary & Question

Key Concepts in Major Histocompatibility Complex (MHC)

1. Ag presentation to TCR is mediated by Two classes of MHC molecules. - Class-I MHC => peptides from cytosolic (intracellular) proteins => CD8 T cells - Class-II MHC => peptides from extracellular (exogenous) proteins from phagocytosis => CD4 T cells

2. In humans, the MHC is also called as the HLA (Human Leukocyte Antigen).

3. MHC genes are the most polymorphic genes present in the genome and co-dominantly expressed in each individual.

4. MHC molecules express on the cellular surfaces of only in presence of Ag-peptides. Class-I => all nucleated cells Class-II => APCs (DC, Macrophages & B cells)

TCR-Ag w/ Histocompatibility Complex (MHC)

The Discovery of Major Histocompatibility Complex (MHC)

Histocompatibility genes: George Snell in 1940s

=> tumors or tissues => same strain, OK => foreign strains,

No

For their work leading

to the discoveries of MHC (mouse) and

HLA (human).

- Immune recognition

=> The foundation of adaptive immunity

- Transplantation

Schematic maps of human & mouse MHC loci

Class-I vs. Class-II MHC moleculeClass-I vs. Class-II MHC molecule

Structure of Class-I MHC moleculeStructure of Class-I MHC molecule

domains are polymorphic and form the peptide-binding cleft.

domain is conserved among all MHC class-I, and folds into an Ig domain for CD8 binding.

Structure of Class-II MHC moleculeStructure of Class-II MHC molecule

domains are polymorphic and form the peptide-binding cleft.

domain is conserved among all MHC class-II, and folds into an Ig domain for CD4 binding.

Polymorphic residuePolymorphic residues s of MHC moleculesof MHC molecules

In Class-I, polymorphic residues => the peptide-binding cleft formed by domains

In Class-II, polymorphic residues => the peptide-binding cleft formed by domainsIn this case HLA-DR, polymorphism is on doma

in

MHC genes are highly PolymorphiMHC genes are highly Polymorphicc

Expression of MHC alleles is co-dominantExpression of MHC alleles is co-dominant

Polymorphism & Polygeny both coPolymorphism & Polygeny both contribute to the MHC diversityntribute to the MHC diversity

Gene conversion Gene conversion creates new alleles creates new alleles in MHC genesin MHC genes

=> Copying sequences => Copying sequences from from one MHC gene to one MHC gene to

anotheranother

Gene recombination creates new Gene recombination creates new alleles in MHC genesalleles in MHC genes

MHC MHC expression expression on cells-Ion cells-I

MHC MHC expression expression on cells-IIon cells-II

Expression of MHC molecules is increased by cytokines produced during innate & adaptive immune cells, e.g. IFN

Features of Peptide-MHC interactions

1. MHC molecules show a broad spectrum for peptide binding,

in contrast to the fine specificity of Ag recognition by Ab.

2. Peptide-MHC interactions are non-covalent and mediated by

residues both in the peptides and in the clefts of MHC molecules.

3. Each MHC molecule binds one peptide at a time but can bind

many “different peptides”.

4. MHC molecules DO NOT discriminate between “Foreign Peptides” & “Self Peptides”.

OutlineOutline• Structures & Features of T-cell antigen

receptor (TCR)

• Structures & Features of Major Histocompatibility Complex (MHC)

• Antigen presentation to T cellsAntigen presentation to T cells

• Summary & Question

Key Concepts in Ag presentation between APCs & T cells

1. Most T cells recognize only peptides, whereas B cells can recognize peptides, lipids, nucleic acids,….etc. NK-T cells can recognize lipids.

2. T cells only recognize peptides displayed by MHC molecules on Ag-presenting cells (APCs).

3. APCs are responsible for capturing and displaying different Ags to T cells.

4. APCs serve two key functions for T cell activation: 1st function => process protein Ags to small peptides => form & present the peptide-MHC complex to T cells 2nd function => provide 2nd co-stimulatory signals, e.g. Cytokines & Surface Molecules

Features of Ag recognition by T cells

T cells require APCs to respond to a specific Ag

Functions of different APCs

Features of different APCs

Dendritic Dendritic cells –cells –The Most The Most effective effective APCsAPCs1. Located at common

sites of entry of microbes

2. Express receptors to capture microbes.

3. Migrate preferentially to T- cell zones in LNs.

4. Mature DCs express high levels of costimulators => T-cell activation.

Overview of Dendritic cells in Overview of Dendritic cells in Ag capture & presentationAg capture & presentation

MHC Restriction of MHC Restriction of cytotoxic T cellscytotoxic T cells

MHC Restriction-IIMHC Restriction-II

For their work leading to the

discoveries regarding the specificity of cell

mediated immunity=>MHC-restriction for T

cell recognition => Adaptive immunity

Class I vs Class II MHC pathway

The Class II MHC pathway of Ag Presentation

The Class I MHC pathway of Ag Presentation

Pathogen presentation by MHCsPathogen presentation by MHCs

Ag Presentation to different T cell subsets

SUMMARY1. TCR functions to recognize Ag peptides presented by MHC complexes => Ag peptide specificity => MHC restriction

2. Two classes of MHC molecules. - Class-I MHC => peptides from cytosolic (intracellular) proteins => CD8 T cells - Class-II MHC => peptides from extracellular (exogenous) proteins from phagocytosis => CD4 T cells

3. APCs serve two key functions for T cell activation: 1st function => process & present Ag peptides w/MHC to

T cells 2nd function => provide 2nd co-stimulatory signals, ex. cytokines & surface molecules

QuestionsQuestions

What is the Bare LymphocyteSyndrome?

What is the advantage of MHC Polymorphism? Is that good if MHC is as diverse as Ig or TCR?