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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
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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
Outline • Structures & Features of T-cell antigen receptor (TCR) • Structures & Features of Major Histocompatibility Complex (MHC) • Antigen Presentation to T cells • Summary & Question
Key Concepts in T-Cell Receptor (TCR)-I 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: ab TCR and gd TCR 2. TCR functions to recognize Ag peptides and then to activate T cells => Adaptive immunity 3. Ag recognition by ab 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 Va and Vb regions.
Key Concepts in TCR-II 5. Like Ab (or BCR), TCR diversity is generated by VDJ recombination. 6. gd T cells function differently from ab T cells in MHC- independent manner.
Similarities & Differences between T-cell Receptor (TCR) and Ab
Murine T-cell Receptor (TCR) genes 1. Two types of TCR, ab and gd, serve distinct functions 2. VDJ recombination for TCR
TCR & Accessory Molecules Accessory Molecules -Help T cells in response to a specific Ag 1. CD3 (e, g, d ) and z 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 Complex TCR/CD3 Complex: 1. TCRab dimer + multiple CD3 dimers - CD3eg dimer - CD3ed dimer - CD3zz dimer 2. The ITAM motif on CD3 => Signaling Transduction
Interaction between innate and& adaptive immunity 1. Innate immunity => Ag presentation (by Dendritic cells) 2. Adaptive immunity => Ag recognition (by T & B lymphocytes)
Binding of a TCR to a peptide-MHC complex Side Front
Outline • Structures & Features of T-cell antigen receptor (TCR) • Structures & Features of Major Histocompatibility 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)
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
Structure of Class-I MHC molecule a1a2domains are polymorphic and form the peptide-binding cleft. a3domain is conserved among all MHC class-I, and folds into an Ig domain for CD8 binding.
Structure of Class-II MHC molecule a1b1domains are polymorphic and form the peptide-binding cleft. b2domain is conserved among all MHC class-II, and folds into an Ig domain for CD4 binding.
Polymorphic residues of MHC molecules In Class-I, polymorphic residues => the peptide-binding cleft formed bya1a2 domains In Class-II, polymorphic residues => the peptide-binding cleft formed bya1b1 domains In this case HLA-DR, polymorphism is on b1domain
Polymorphism & Polygeny both contribute to the MHC diversity
Polymorphism vs Polygeny of MHC 1. MHC molecules are polygenic. Every individual contains several different MHC-I & MHC-II genes with wide ranges of peptide-binding specificity. => Personal protection 2. MHC is highly polymorphic. Multiple variants of each MHC gene within the population function as a whole.
Gene conversion creates new alleles in MHC genes => Copying sequences from one MHC gene to another
MHC expression on 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”.
Outline • Structures & Features of T-cell antigen receptor (TCR) • Structures & Features of Major Histocompatibility Complex (MHC) • Antigen 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
Dendritic cells –The Most effective APCs 1. 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.
For their work leading to the discoveries regarding the specificity of cell mediated immunity =>MHC-restriction for T cell recognition => Adaptive immunity