Adaptive immunity antigen recognition Y Y Y Y Y Y Y Y Y invading viruses or bacteria macrophage Humoral Immunity (Antibody repsonse) Cell-Mediated Immunity (CMI) antigen recognition cytotoxic T lymphocyte B lymphocyte signals signals helper T lymphocyte Y Y Y Y Y Y Y Y Y killing of infected cells antibody production

Antigens Proteins only, for T cells Proteins, some polysaccharides for B cells virus antigens epitope T cell

Antigen processing and presentation T cells only see Ag when presented by an APC for TH: APC = macrophage or DC, exogenous Ag, MHC II for TC: APC = infected cell, endogenous Ag, MHC I MHC Ag TCR T processing presentation (bound to MHC) CD4 or 8

Antigen processing and presentation What kinds of cells are APCs for exogenous antigens? How do the APCs recognize the antigens? What are MHC proteins? How does MHC II recognize an antigen peptide? How does MHC II get loaded with the antigen peptide? How does the T cell recognize the presented Ag? Where does T-cell receptor diversity come from? What about endogenous Ag and MHC I?

What kinds of cells are APCs for exogenous antigens? Immature DCs in epithelia Langerhans cells MHC not expressed Macrophage-like cells GALT, SALT, MALT…

How do the APCs recognize the antigens? Pattern receptors: TLRs Mannose receptor etc. Endocytosis Pinocytosis

How do the APCs recognize the antigens? Activated by inflammatory cytokines Migration to lymph nodes Lose adhesion Express CCR7 Maturation: express MHC

How does MHC II recognize an antigen peptide? Major histocompatibility complex Large genetic locus on chromosome 6 (HLA) Highly polymorphic 3 class I genes, 2 alleles each → 6 different proteins 3 class II α genes, 3 β genes, 2 alleles each → 18 proteins Immunological “fingerprint”

MHC structure class I class II

MHC structure a chain – multiple alleles class I class II

MHC structure b chain – multiple alleles class I class II

MHC structure b2 microglobulin – same for every MHC I class I class II

MHC structure Immunoglobulin fold class I class II

MHC structure CD4 binding site (TH) – same for all MHC II class I class II

MHC structure CD8 binding site (TC) – same for all MHC I class I class II

MHC structure Peptide-binding region class I class II chime tutorial

How does MHC II get loaded with the antigen peptide? How is MHC class II synthesized and localized? Given its synthesis pathway, where must it encounter Ag? What restrictions should there be on the peptides it encounters?

How does the T cell recognize the presented Ag? “Immunological synapse” – clustering of proteins in small area Antigen-specific T-cell receptor binds Ag + MHC CD4 binds MHC class II CD28 binds B7 co-stimulator

Where does T-cell receptor diversity come from? Multiple of TCR subunit genes in genome Recombination during T-cell development in bone marrow cleavage by VDJ recombinase (RAG-1 + RAG-2) ligation

Where does T-cell receptor diversity come from? Combinatorial diversity Junctional diversity

Where does T-cell receptor diversity come from? Selection during development

How does MHC I get loaded with antigen peptide? MHC I recognizes endogenous Ag: synthesized in the cell Why would Ag be made in the cell? Where would we want to recognize Ag peptides?