--- module: 093-02 language: en chapter: 93 title: "Mechanistic Immunology: Recognition, Activation, and Effector Systems" module_title: "Antigen processing, major histocompatibility complexes, and lymphocyte activation" source_sha256: 93b6083bea06b12d043a2bdb71127548c86f1d6a07f1bc7d8511352328f54bc9 --- # Antigen processing, MHC, and lymphocyte activation ## Adaptive recognition and HLA ### Clonal receptors from somatic rearrangement ### T cells see presented peptide, B cells native antigen ### Costimulation and cytokines supply context ### HLA encoded on chromosome six #### Class one: HLA-A, B, C #### Class two: HLA-DP, DQ, DR ### Polymorphism aids population pathogen recognition #### Complicates transplantation and disease links ### Co-dominant expression of inherited alleles ## MHC class one pathway ### Heavy chain, beta-two microglobulin, peptide ### Nearly all nucleated cells and platelets ### Closed groove holds short peptides ### CD8 T cells survey for intracellular change ### Proteasome, immunoproteasome in inflammation ### TAP carries peptides into the ER ### Chaperones load, edit, trim ### Stable complexes travel via Golgi to surface ### Defects impair antiviral defence ## Evasion and cross-presentation ### Viruses block proteasome, TAP, loading, surface ### Low class one removes natural killer inhibition #### Evolutionary tension ### Dendritic cells present external antigen on class one #### Primes killers against non-infecting viruses, tumours ## MHC class two pathway ### Alpha and beta chains ### Professional presenting cells, inducible elsewhere ### Open groove binds longer peptides ### Invariant chain blocks groove, routes to endosomes #### Degraded to CLIP fragment #### HLA-DM removes CLIP and edits loading #### HLA-DO modulates in selected cells ### Autophagy delivers intracellular antigen ### B cells present peptides of captured antigen #### Linked recognition explains carrier effects ### CD4 T cells coordinate responses ## T-cell activation ### Alpha-beta receptor with CD3 chains ### Recognises combined peptide-MHC surface ### CD4 binds class two, CD8 class one ### Modest affinity, sensitive via microclusters ### CD28 binds B7 as costimulation #### Without it: anergy, deletion, tolerance ### CTLA4 and PD1 restrain activation ### Calcineurin-NFAT, MAP kinase, NF-kappa B #### Induce interleukin 2 and high-affinity receptor #### Drugs target calcineurin, mTOR, nucleotides ## Trafficking and T-cell fates ### Enter nodes via high endothelial venules ### Unactivated cells exit on S1P gradients ### Activation retains, then changes homing ### Type 1: interferon gamma, intracellular pathogens ### Type 2: interleukins 4, 5, 13, helminths ### Type 17: interleukins 17, 22, barriers ### Follicular helpers give CD40 ligand ### FOXP3 regulatory cells suppress ### Categories flexible, mixed states occur ### CD8 kill via perforin, granzyme, death receptors ### Chronic antigen causes exhaustion #### Checkpoint blockade reinvigorates, risks inflammation ## B-cell activation ### Membrane immunoglobulin binds native antigen ### CD19 co-receptor amplifies complement-tagged signal ### T-dependent: present peptide to follicular helpers #### Extrafollicular: plasmablasts and IgM #### Germinal centres: affinity, switching, memory ### T-independent: rapid but little memory #### Especially weak in young children #### Protein conjugation recruits T-cell help ## Expansion, memory, and synapse ### Clonal expansion then contraction ### Memory alters threshold, location, metabolism ### Memory need not be sterilising ### Synapse: LFA1-ICAM stabilises contact ### Granules polarised to limit bystander damage ## Broad activation, HLA, and context ### Superantigens crosslink outside peptide groove #### Many clones, massive cytokine release ### HLA associations neither necessary nor sufficient #### Typing guides transplantation, drug safety ### Dose, persistence, route shape fate ### Adjuvants activate sensors, not specificity ### Specificity, danger, programme, destination, duration