USMLE Step 1 · Immunology

MHC class I vs MHC class II

How to tell MHC class I and MHC class II apart when a board question makes them look alike.

Fastest separator

MHC I presents endogenous antigen to CD8 on nucleated cells; MHC II presents exogenous antigen to CD4 on professional APCs.

Side by side

MHC class IMHC class II

Key clue

MHC class I is expressed on nearly all nucleated cells, presents endogenous cytosolic peptides, and is recognized by CD8 cytotoxic T cells.

MHC class II is expressed on professional antigen-presenting cells, presents exogenous peptides from endosomes, and is recognized by CD4 helper T cells.

Mechanism

Proteasome-derived peptides enter the endoplasmic reticulum through TAP and load onto MHC I with beta-2 microglobulin.

Endocytosed proteins are processed in acidified vesicles and loaded onto MHC II after invariant chain/CLIP removal.

Labs and tests

Viral cytosolic antigen, TAP, beta-2 microglobulin, and CD8 restriction support MHC I.

Dendritic/macrophage/B-cell presentation, exogenous antigen, invariant chain, and CD4 restriction support MHC II.

The trap

Both MHC classes present peptide to T cells, but they differ in antigen source, presenting cell, and T-cell partner. MHC class I is on ALL nucleated cells, presents ENDOGENOUS peptides (viral proteins synthesized inside the cell, tumor antigens, cytosolic proteins) loaded onto MHC I in the endoplasmic reticulum via the TAP transporter, and partners with CD8 T cells. MHC class II is on PROFESSIONAL APCs only (dendritic cells, macrophages, B cells), presents EXOGENOUS peptides (phagocytosed bacteria, internalized antigens) loaded onto MHC II in the late endosome / MIIC compartment after the invariant chain (CLIP) is removed by HLA-DM, and partners with CD4 T cells. The 'rule of 8': CD8 times MHC1 = 8 = CD4 times MHC2 (so CD8 sees MHC I and CD4 sees MHC II).

Watch it explained

60-second lessonMHC Class I vs Class II: The Rule of 8 (USMLE Step 1)

Quiz yourselfMHC Class I or Class II? 6-Second Immunology Pop Quiz (USMLE Step 1)

Test it now

The repair move

For MHC questions, ask endogenous versus exogenous antigen, then match CD8 versus CD4.

Try a free question

Core

A virus-infected hepatocyte produces viral proteins in the cytoplasm. These proteins are degraded by the proteasome, transported into the endoplasmic reticulum by TAP1/TAP2, loaded onto a specific MHC molecule with beta-2 microglobulin, and presented at the cell surface to CD8 T cells. Which MHC class is this?

Show answer and explanation

Answer: A. MHC class I. MHC class I is expressed on virtually all nucleated cells and presents endogenous cytosolic peptides (viral proteins, tumor antigens) to CD8 T cells. Loading pathway: proteasome -> TAP1/TAP2 transporter -> ER -> MHC I with beta-2 microglobulin -> cell surface. Loss of MHC I (downregulation by tumors and viruses) triggers NK cell recognition.

Why the other choices are tempting

B. MHC class II presents exogenous antigens on professional APCs to CD4 T cells, not endogenous cytosolic antigens.
C. CD1 presents lipid antigens to NKT cells.
D. MR1 presents microbial-derived vitamin B metabolites to MAIT cells.
E. Non-classical HLA-G is expressed on placental trophoblasts to inhibit maternal NK cells, not the standard antigen presentation pathway.

Flashcards

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What clue supports MHC class I?

Choose MHC class I when the stem gives this pattern: MHC class I is expressed on nearly all nucleated cells, presents endogenous cytosolic peptides, and is recognized by CD8 cytotoxic T cells.

What clue supports MHC class II?

Choose MHC class II when the stem gives this contrasting pattern: MHC class II is expressed on professional antigen-presenting cells, presents exogenous peptides from endosomes, and is recognized by CD4 helper T cells.

Quick answers

What is the fastest way to tell MHC class I from MHC class II?