STEPTRACKERIMMUNOLOGY + GENETICS | ADAPTIVE IMMUNITY | HIGH-YIELD REVIEW

MHC & Antigen Presentation

T cells only see peptides displayed on MHC. Where the protein came from — inside the cell or swallowed from outside — decides which MHC carries it and which T cell responds.

FOCUS ON

MHC I (HLA-A, -B, -C): on all nucleated cells (not RBCs); heavy chain + β2-microglobulin; presents endogenous (cytosolic, viral, tumor) peptides made by the proteasome, moved into the ER by TAP → CD8⁺ T cells. MHC II (HLA-DR, -DP, -DQ): on APCs (DCs, macrophages, B cells); α + β chains; invariant chain blocks the groove until the endosome, CLIP swapped out by HLA-DM; presents exogenous peptides → CD4⁺ T cells. Cross-presentation: DCs put exogenous antigen on MHC I to prime CD8⁺ cells against viruses and tumors. Evasion: viruses ↓ MHC I (HSV, CMV, HIV nef, adenovirus) → NK cells take over. HLA genes on chromosome 6, codominant, inherited as haplotypes (sibling match 25%).

FEATURE

MHC CLASS I

MHC CLASS II

CLINICAL LINK

Genes

HLA-A, -B, -C

HLA-DP, -DQ, -DR

Chromosome 6p · codominant

Expressed on

All nucleated cells and platelets

APCs: DCs, macrophages, B cells (thymic epithelium)

RBCs lack MHC I → malaria can hide

Structure

α heavy chain + β2-microglobulin; closed groove (8–10 aa)

α + β chains; open groove (13–25 aa)

β2-microglobulin ↑ in myeloma, dialysis amyloid

Antigen source

Endogenous: cytosolic proteins, viruses, tumor antigens

Exogenous: phagocytosed microbes, extracellular proteins

—

Processing

Ubiquitin → proteasome → TAP transporter into ER → loaded on MHC I

Endosome/lysosome proteases; invariant chain (CLIP) removed by HLA-DM

TAP deficiency → low MHC I (bare lymphocyte type 1)

T cell recognized

CD8⁺ cytotoxic T cell

CD4⁺ helper T cell

MHC II deficiency → no CD4⁺ cells

Recognized by NK cells

Yes — inhibitory KIRs read MHC I

Missing MHC I → NK killing

Up-regulated by

IFN-α/β, IFN-γ

IFN-γ

—

Cross-presentation

DCs load exogenous antigen onto MHC I

—

Basis of tumor and some vaccine immunity

Superantigens

—

Cross-link MHC II outside the groove with TCR Vβ → massive polyclonal T-cell activation

TSST-1, SpeA → toxic shock

Viral evasion

HSV, CMV, adenovirus, HIV (nef) ↓ MHC I

—

Leaves cells open to NK killing

Transplant matching

HLA-A, -B

HLA-DR (most important)

Each sibling: 25% chance of identical match

Picture it — two presentation pathways

MHC I pathwayCytosolic proteins are cut by the proteasome, carried into the ER by TAP and loaded onto MHC I for CD8⁺ T cells.

MHC II pathwayEngulfed microbes are digested in endosomes; MHC II arrives from the ER with the invariant chain, swaps CLIP for peptide and shows it to CD4⁺ T cells.

Schematic diagrams, not to scale.

Mechanism — endogenous pathway

Viral protein in cytosol

→

Proteasome → peptides

→

TAP → ER

→

MHC I + β2m → surface

→

CD8⁺ T cell kills

Exogenous route: phagosome → lysosomal proteases → peptide replaces CLIP on MHC II → CD4⁺ help.

Common HLA associations

HLA

DISEASE

NOTE

B27

Ankylosing spondylitis, reactive arthritis, psoriatic, IBD arthritis

Seronegative spondyloarthropathies

DQ2 / DQ8

Celiac disease

DQ8 also type 1 diabetes

DR3 / DR4

Type 1 diabetes

DR3: Graves, SLE; DR4: RA

B57:01

Abacavir hypersensitivity

Test first

B15:02

Carbamazepine SJS/TEN

Southeast Asian ancestry

DR2 (DR15)

Multiple sclerosis, Goodpasture, narcolepsy

—

Hereditary hemochromatosis

—

How it's tested

COMMON CONFUSIONMHC I is read by CD8⁺ cells and MHC II by CD4⁺ cells — CD4 and CD8 bind the MHC molecule itself, not the peptide.

THE TRAPA virus that hides by lowering MHC I escapes CD8⁺ T cells but invites NK-cell attack.

YOUR APPROACHWhere is the antigen (cytosol vs vesicle) → which MHC → which T cell → what kind of response.

If you see… think…

Cells lacking MHC I → red blood cells

Protein that pairs with the MHC I heavy chain → β2-microglobulin

Transporter moving peptides into the ER → TAP

Protein blocking the MHC II groove until the endosome → invariant chain (CLIP)

Viral peptide presented to CD8⁺ T cells → MHC I

Phagocytosed bacterial peptide presented to CD4⁺ → MHC II

TSST-1 binding MHC II outside the groove → superantigen

HLA chromosome → 6

Back pain with uveitis, HLA-B27 → ankylosing spondylitis

Rash on carbamazepine in a Han Chinese patient → HLA-B*15:02