MHC questions are “free points” on Step exams once you can draw the pathways from memory. Here’s a quick, shareable draw-it-out method (plus mnemonics and one-liners) to lock down MHC I vs MHC II in under a minute.
The 10-second one-liners (what you should say in your head)
- MHC I: “Endogenous (inside) peptides → CD8 T cells → kill infected/tumor cells.”
- MHC II: “Exogenous (outside) peptides → CD4 T cells → activate immune response (help).”
Draw-it-out method (sketch this on your scratch paper)
Step 1: Draw two boxes: “Inside the cell” vs “Outside the cell”
- Left: Inside (cytosol)
- Right: Outside (phagosome/endosome)
Now map each to its MHC.
MHC I — the “inside job” pathway (Endogenous → CD8)
What to draw
- A virus/tumor protein in the cytosol
- An arrow to proteasome (protein shredder)
- Peptides go through TAP into the RER
- Peptides load onto MHC I
- MHC I goes to the cell surface
- A CD8 T cell binds and kills the cell
Tiny diagram
Cytosol → Proteasome → TAP → RER → MHC I → Surface → CD8
Mnemonic
- “I = In” (endogenous = inside)
- “8 = ate” → CD8 “ate” the infected cell (kills it)
- TAP = the transporter that “taps” peptides into the RER
High-yield facts (Step-ready)
- Expressed on: All nucleated cells (RBCs are anucleate → no MHC I)
- Presents to: CD8+ cytotoxic T cells
- Made where? MHC I is synthesized in the RER
- Peptide source: Endogenous proteins (viral, tumor, misfolded self)
- Key proteins: Proteasome, TAP
- HLA types (humans): HLA-A, HLA-B, HLA-C
MHC II — the “outside pickup” pathway (Exogenous → CD4)
What to draw
- An APC eating something from outside (phagocytosis/endocytosis)
- Inside an endosome/lysosome: antigen gets chopped
- MHC II is made in the RER but arrives with a blocker
- Blocker gets removed in the endosome → peptides load
- MHC II goes to the cell surface
- A CD4 T cell binds and helps (cytokines, activation)
Tiny diagram
Outside → Endosome/Lysosome → MHC II loading → Surface → CD4
Mnemonic
- “II = out” (sounds like “two” → think two hands picking up from outside)
- “4 = helper” → CD4 helps (activates macrophages, B cells)
- Invariant chain = the “placeholder” that prevents premature peptide loading in the RER
High-yield facts (Step-ready)
- Expressed on: Professional APCs
Dendritic cells, Macrophages, B cells (“DMB”) - Presents to: CD4+ helper T cells
- Peptide source: Exogenous proteins (bacteria, toxins, extracellular pathogens)
- Key proteins:
- Invariant chain blocks peptide binding in the RER
- HLA-DM removes CLIP and helps load the exogenous peptide
- HLA types (humans): HLA-DP, HLA-DQ, HLA-DR
The “2×2” memory table (print this into your brain)
| Feature | MHC I | MHC II |
|---|---|---|
| Antigen source | Endogenous (cytosolic) | Exogenous (endosomal) |
| Where expressed | All nucleated cells | Professional APCs (DMB) |
| Presented to | CD8 cytotoxic T cells | CD4 helper T cells |
| Key processing | Proteasome → TAP → RER | Endosome/lysosome, Invariant chain, HLA-DM |
| Human HLA | A, B, C | DP, DQ, DR |
Classic USMLE “gotchas” (very testable)
1) Why don’t RBCs present antigen?
- No nucleus → no MHC I (and they aren’t APCs → no MHC II)
2) What cell is the best APC to activate naïve T cells?
- Dendritic cell (high yield for initiating adaptive immunity)
3) If a virus hides in the cytosol, which pathway matters most?
- MHC I → CD8 (kill the infected cell)
4) If a bacterium is phagocytosed by a macrophage, which pathway?
- MHC II → CD4 (activate macrophage + orchestrate response)
Quick self-check (one question)
You see a question stem: “APC ingests bacteria → presents antigen to a T cell → cytokines activate macrophages.”
Answer in your head: MHC II → CD4