Lecture 19: MHC Structure and Function (+ Natural Killer Cells)

Major Histocompatibility Complex (MHC)

• also known as HLA (human leukocyte antigen) in humans

• exists in many alternative (allelic) forms

• most polymorphic genes found within our genome

• MHC-I - expressed by all nucleated cells

  • humans express 3 ‘isotypes’: HLA-A, B, and C

• MHC-II - expressed by antigen presenting cells (DC, B, monocytes, and macrophages

  • humans express 3 ‘isotypes’: HLA-DR, DP, and DQ

• most important alleles to match in a transplant: HLA-A, HLA-B, and HLA DR genes

  • remember that humans are diploid so we have 12 genes (6 alleles total but 12 overall)

• Polymorphism - presence of multiple variants of MHC genes

• Polygeny - multiple genes contribute to MHC (allowing for diverse antigen presentation and immune response)

• Polymorphism + Polygeny = all 12 alleles expressed all at once

  • ethnic based alleles give Europeans genetic advantage to transplant compared to ethnic minorities (like maori)

MHC structure

MHC-1 (~8-9 amino acids) (shorter, constricted on one end)

• Heterodimer

• alpha chain and beta2-microglobulin

• one transmembrane region

• polymorphisms on alpha 1 and alpha 2 subunits

MHC-2 (15-25 amino acids) (not constricted, longer)

• heterodimer

• alpha chain and beta chain

• two transmembrane regions

• Polymorphism on beta 1 subunit

Anchor Residues

anchors peptides into MHC structure

MHC-1

• anchors short peptides

• lock in certain amino acids

MHC-2

• anchors (but not as much)

• non-covalent binding

TCR recognition

the TCR recognizes MHC and peptide as a combined complex (the peptide on its own will not activate a T-cell, neither will an empty MHC

polymorphism determines how TCR binds to MHC-peptide complex

MHC class 1

• displays endogenous antigen 

• recognized by TCR on CD8 T cells

  • allows CD8 to visualize what is happening in the cell of the MHC-1 receptor (intracellular infection)

• almost exclusively self-peptide displayed

• Presentation pathway:

  1. foreign protein forced through proteasome, becomes peptide

  2. peptide goes to ER

  3. MHC-1 parts hanging out in ER (unstable)

  4. Peptide binds to MHC-1 w/ help of chaperone protein making MHC-1 stable

  5. MHC/peptide complex goes through secretory pathways and onto cell surface

     • the MHC complex has transmembrane domain which makes MHC stop at membrane and anchor at surface

  6. CD8 T-cell activated by MHC complex and kills infected cells

Cross presentation of exogenous antigen

occurs when exogeneous antigen becomes endogenous and is displayed on MHC1 instead of MHC2

MHC class 2

antigen presentation pathway:

• synthesized in ER 

• attached to MHC2 BUT also loaded with phagolysosome (very acidic and causes peptide degradation)

• once stable brought to surface + binds w/ CD4 T cell

Superantigens

• proteins produced by Gram + bacteria that interact with MHC2 and the TCR to induce massive T-cell activation

• results in expansion of whole T cell receptor families of both CD4 and CD8 T cells (stimulate ~30% of CD4 and CD8 T cells)

  • T-cells quickly get worn out → organ failure

  • bacteria exploits the T-cell uncoordinated activity and invades isolated parts of body (results in vascular leakage which allows the microbe to disseminate)

  • can result in toxic shock

Pathway of Toxic shock

1. Local Inflammation - monocyte activation, endothelial cell activation, and complement activation (occurs in low quantities)

2. systemic effects - induces fever and acute-phase reactants in liver (occurs in moderate quantities)

3. Toxic Shock - low cardiac output, low peripheral resistance (high quantities)