Introduction to Immunology

Introduction to ImmunologyJianzhu ChenDepartment of BiologyMassachusetts Institute of Technologyjchen@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.

Principle of the Adaptive ImmunityWhat 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?

Key molecules and cells of the adaptive immunityB cellsT cellsAntigen-presenting cells (APC)Dendritic cells (DC)MacrophageB cells3 molecules3 cell types4 cardinal features

Antigen recognition by BCR and TCR

TCR-peptide-MHC (pMHC) interaction

peptideMHC StructureWiley et al. 1987

TCR-pMHC interactionExtensive contacts:between TCR and peptidebetween TCR and MHCTCR 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)

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

MHC StructureSimilar to Ig and TCR, belongs to the Ig superfamily

Peptide-binding proteinsPeptide is part of the stable structure (heterotrimers)MHC Structure

MHC Structure

MHC Structure

Class IClass IIPeptide binding domain1 / 21 / 1Peptide binding cleftClosed at both endsOpen

MHC Structure

Class IClass IIPeptide binding domain1 / 21 / 1Peptide binding cleftClosed at both endsOpenLength of peptide8-1013-15 (hanging out)

MHC Structure

Class IClass IIPeptide binding domain1 / 21 / 1Peptide binding cleftClosed at both endsOpenLength of peptide8-1013-15 (hanging out)p-MHC interactionAnchor residues 2 & 9No anchor residue

MHC Structure

Class IClass IIPeptide binding domain1 / 21 / 1Peptide binding cleftClosed at both endsOpenLength of peptide8-1013-15 (hanging out)p-MHC interactionAnchor residues 2 & 9No anchor residue

TCR-pMHC interaction

MHC Structure

Class IClass IIPeptide binding domain1 / 21 / 1Peptide binding cleftClosed at both endsOpenLength of peptide8-1013-15 (hanging out)p-MHC interactionAnchor residues 2 & 9No anchor residueSource of peptideCytosolic (endogenous)Endocytic (exogenous)

MHC Structure

Class IClass IIPeptide binding domain1 / 21 / 1Peptide binding cleftClosed at both endsOpenLength of peptide8-1013-15 (hanging out)p-MHC interactionAnchor residues 2 & 9No anchor residueSource of peptideCytosolic (endogenous)Endocytic (exogenous)ExpressionAll nucleated cellsAntigen presenting cells (DC, B, MO)

MHC Structure

Class IClass IIPeptide binding domain1 / 21 / 1Peptide binding cleftClosed at both endsOpenLength of peptide8-1013-15 (hanging out)p-MHC interactionAnchor residues 2 & 9No anchor residueSource of peptideCytosolic (endogenous)Endocytic (exogenous)ExpressionAll nucleated cellsAntigen presenting cells (DC, B, MO)T cell recognitionCD8 (Cytolytic)CD4 (T helper)

MHC NomenclatureHLA-DP -DQ -DRHLA-A -B -CHumanHuman Leukocyte AntigenClass IIClass IExample: HLA-A2 (or A2), human MHC class I A molecule, allele 2 Haplotype: each set of allelesH2-Kd (Kd)IAdBalb/c H-2d H2-Dd (Dd)IEd H2-Ld (Ld)

MHC FunctionHow can a small number of MHC molecules present a large number of peptides for TCR recognition? PolygenicPossible MHC class I combinations in one individual: 2A + 2B + 2C = 6

MHC FunctionHow can a small number of MHC molecules present a large number of peptides for TCR recognition? Polygenic PolymorphicPresence of multiple alleles at a given locus within a speciesPossible MHC class I combinations in the human population: 470 x 110 x 240 = 1,240,800

MHC FunctionHow can a small number of MHC molecules present a large number of peptides for TCR recognition? Polygenic PolymorphicExtremely polymorphic5% 20 a.a.

MHC FunctionHow 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

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