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

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. Innate Adaptive Cells Ag receptors Ag recognition Speed Memory

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

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

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

Antigen recognition by BCR and TCR

TCR-peptide-MHC (pMHC) interaction

MHC Structure Wiley et al. 1987 peptide Kuby 7-10

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

TCR-pMHC interaction

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)

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

MHC Structure Similar to Ig and TCR, belongs to the Ig superfamily a Kuby 4-20

Two compartments of the cell

 + 2m (2 microglobulin) MHC Structure Class I  + 2m (2 microglobulin) Simplified: Model: 1 2 3 2m peptide Class II  +  subunits 1 2 1 2 peptide L a2 a1 a3 Tm C Gene: Peptide-binding proteins Peptide is part of the stable structure (heterotrimers)

MHC Structure Class I b2m Class II Peptide binding cleft

MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1 Peptide binding cleft Closed at both ends Open Kuby 7-10

MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1 Peptide binding cleft Closed at both ends Open Length of peptide 8-10 13-15 (hanging out) Kuby 7-12

MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1 Peptide binding cleft Closed at both ends Open Length of peptide 8-10 13-15 (hanging out) p-MHC interaction Anchor residues 2 & 9 No anchor residue Cell MHC Denature Peptide mass spectrometry Peptide Sequence

MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1 Peptide binding cleft Closed at both ends Open Length of peptide 8-10 13-15 (hanging out) p-MHC interaction Anchor residues 2 & 9 No anchor residue

TCR-pMHC interaction

MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1 Peptide binding cleft Closed at both ends Open Length of peptide 8-10 13-15 (hanging out) p-MHC interaction Anchor residues 2 & 9 No anchor residue Source of peptide Cytosolic (endogenous) Endocytic (exogenous)

MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1 Peptide binding cleft Closed at both ends Open Length of peptide 8-10 13-15 (hanging out) p-MHC interaction Anchor residues 2 & 9 No anchor residue Source of peptide Cytosolic (endogenous) Endocytic (exogenous) Expression All nucleated cells Antigen presenting cells (DC, B, MO)

MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1 Peptide binding cleft Closed at both ends Open Length of peptide 8-10 13-15 (hanging out) p-MHC interaction Anchor residues 2 & 9 No anchor residue Source of peptide Cytosolic (endogenous) Endocytic (exogenous) Expression All nucleated cells Antigen presenting cells (DC, B, MO) T cell recognition CD8 (Cytolytic) CD4 (T helper)

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

MHC Function How can a small number of MHC molecules present a large number of peptides for TCR recognition? Polygenic HLA-C HLA-B HLA-A DR 1a 3b 2a 2b DQ DP Possible MHC class I combinations in one individual: 2A + 2B + 2C = 6

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-C HLA-B HLA-A DR 1a 3b 2a 2b DQ DP 240 470 110 2 20 350 45 19 89 Possible MHC class I combinations in the human population: 470 x 110 x 240 = 1,240,800

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

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 >2,000 peptides per class I molecule >> 2,000 peptides per class II molecule ~105 molecules per cell HLA-C HLA-B HLA-A DR 1a 3b 2a 2b DQ DP 240 470 110 2 20 350 45 19 89