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Introduction to Immunology Jianzhu Chen Department of Biology Massachusetts Institute of Technology Principles of adaptive immunity TCR recognition.

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Presentation on theme: "Introduction to Immunology Jianzhu Chen Department of Biology Massachusetts Institute of Technology Principles of adaptive immunity TCR recognition."— Presentation transcript:

1 Introduction to Immunology Jianzhu Chen Department of Biology Massachusetts Institute of Technology Principles of adaptive immunity TCR recognition Antigen presentation and processing Host defense against viruses

2 InnateAdaptive Cells Ag receptors Ag recognition Speed Memory Innate immunity: Preformed, non-specific effectors. Adaptive immunity: Immune mechanisms that are mediated by T and B lymphocytes and that change in response to infection.

3 Principle of the Adaptive Immunity What is fundamental challenge faced by the immune system? Fact: Strategy: Solution:

4 What are the consequences of using V(D)J recombination to create antigen receptor diversity?

5  V V V V V Key molecules and cells of the adaptive immunity B cellsT cells Antigen-presenting cells (APC) Dendritic cells (DC) Macrophage B cells 3 molecules 3 cell types 4 cardinal features

6 Antigen recognition by BCR and TCR

7 TCR-peptide-MHC (pMHC) interaction

8 peptide MHC Structure Wiley et al. 1987

9 TCR-pMHC interaction Extensive contacts: between TCR and peptide between TCR and MHC TCR molecules are evolved to bind to MHC

10 TCR-pMHC interaction

11 Major Histocompatibility Complex (MHC) 1930s: Peter Gorer identified four groups (I, II, III, and IV) of blood cell antigens in inbred mice. 1950s: George Snell established the group II antigens mediate rejection of transplanted tumors and other tissues. Histocompatibility antigens (H-2 in mouse) Human Leukocyte Antigens (HLA in human)

12 Zinkernagel & Doherty, 1975 MHC Restriction MHC type determine the ability of T cell response.

13 MHC Structure Similar to Ig and TCR, belongs to the Ig superfamily 

14 Two compartments of the cell

15 Peptide-binding proteins Peptide is part of the stable structure (heterotrimers) Class I  +  2 m (  2 microglobulin) Simplified: Model: 11 22 33 2m2m peptide Class II  +  subunits 11 22 11 22 peptide MHC Structure L 22 11 33 Tm CC Gene:

16 MHC Structure Class IIClass I  2m Peptide binding cleft Peptide binding cleft

17 Class IClass II Peptide binding domain  1 /  2  1 /  1 Peptide binding cleft Closed at both endsOpen MHC Structure

18 Class IClass II Peptide binding domain  1 /  2  1 /  1 Peptide binding cleft Closed at both endsOpen Length of peptide (hanging out) MHC Structure

19 Class IClass II Peptide binding domain  1 /  2  1 /  1 Peptide binding cleftClosed at both endsOpen Length of peptide (hanging out) p-MHC interactionAnchor residues 2 & 9No anchor residue MHC Structure Cell MHC Denature Peptide mass spectrometry Peptide Sequence

20 Class IClass II Peptide binding domain  1 /  2  1 /  1 Peptide binding cleftClosed at both endsOpen Length of peptide (hanging out) p-MHC interactionAnchor residues 2 & 9No anchor residue MHC Structure

21 TCR-pMHC interaction

22 MHC Structure Class IClass II Peptide binding domain  1 /  2  1 /  1 Peptide binding cleftClosed at both endsOpen Length of peptide (hanging out) p-MHC interactionAnchor residues 2 & 9No anchor residue Source of peptideCytosolic (endogenous)Endocytic (exogenous)

23 MHC Structure Class IClass II Peptide binding domain  1 /  2  1 /  1 Peptide binding cleft Closed at both endsOpen Length of peptide (hanging out) p-MHC interactionAnchor residues 2 & 9 No anchor residue Source of peptideCytosolic (endogenous) Endocytic (exogenous) ExpressionAll nucleated cellsAntigen presenting cells (DC, B, MO)

24 Class IClass II Peptide binding domain  1 /  2  1 /  1 Peptide binding cleft Closed at both endsOpen Length of peptide (hanging out) p-MHC interactionAnchor residues 2 & 9 No anchor residue Source of peptideCytosolic (endogenous) Endocytic (exogenous) ExpressionAll nucleated cellsAntigen presenting cells (DC, B, MO) T cell recognitionCD8 (Cytolytic)CD4 (T helper) MHC Structure

25 MHC Nomenclature HLA-DP -DQ -DR HLA-A -B -C Human Leukocyte Antigen Class IIClass I Example: HLA-A2 (or A2), human MHC class I A molecule, allele 2 MouseH2-IA -IE H2-K -D -L Haplotype: each set of alleles H2-K d (K d )IA d Balb/c  H-2 d H2-D d (D d )IE d H2-L d (L d )

26 MHC Function How can a small number of MHC molecules present a large number of peptides for TCR recognition? Polygenic HLA-CHLA-BHLA-A DR  DQDP Possible MHC class I combinations in one individual: 2A + 2B + 2C = 6

27 MHC Function How can a small number of MHC molecules present a large number of peptides for TCR recognition? Polygenic Polymorphic Presence of multiple alleles at a given locus within a species HLA-CHLA-BHLA-A DR  DQDP Possible MHC class I combinations in the human population: 470 x 110 x 240 = 1,240,800

28 MHC Function How can a small number of MHC molecules present a large number of peptides for TCR recognition? Polygenic Polymorphic Extremely polymorphic 5%  20 a.a. Differences in amino acids are concentrated in the peptide-binding groove. Different MHC molecules bind to different set of peptides

29 MHC Function How can a small number of MHC molecules present a large number of peptides for TCR recognition? Polygenic Polymorphic Co-expression Presentation of multiple peptides per MHC molecule HLA-CHLA-BHLA-A DR  DQDP >2,000 peptides per class I molecule >> 2,000 peptides per class II molecule ~10 5 molecules per cell


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