MHC I vs MHC II: Draw the Pathways, CD8 vs CD4 & Rule of 8

MHC class I (HLA-A, -B and -C) is found on all nucleated cells and presents peptides made inside the cell to CD8+ cytotoxic T cells: cytosolic proteins are cut by the proteasome, pumped into the endoplasmic reticulum (ER) by TAP and loaded onto an α chain paired with β2-microglobulin. MHC class II (HLA-DP, -DQ and -DR) sits mainly on professional antigen-presenting cells (dendritic cells, macrophages, B cells) and presents peptides from material taken up from outside to CD4+ helper T cells, loaded in endosomes once HLA-DM removes the CLIP placeholder. The rule of 8 locks in the pairing (MHC I × CD8 = 8; MHC II × CD4 = 8), and three exceptions finish the topic: cross-presentation, NK cells and "missing self," and viral evasion.

The rule of 8

• MHC I × CD8 = 8. Class I presents to CD8+ T cells, which kill the presenting cell if the peptide is foreign.
• MHC II × CD4 = 8. Class II presents to CD4+ helper T cells, which coordinate the response, including antibody production by B cells.
• Inside vs outside: class I shows what is in the cytosol (viral, tumor and normal self proteins); class II shows what the cell has eaten.

Draw it out: the sketch in 6 steps

Draw one large cell with a nucleus in the middle, the ER and Golgi above it, the cytosol on the left and an endosome on the right. The left half of your page becomes MHC I, the right half MHC II, and the cell surface at the top is where both meet their T cells.

Left side: MHC I, the inside job

1. Draw a virus in the cytosol making its proteins. Any protein made inside the cell, self or foreign, can be presented.
2. Draw a barrel: the proteasome. It degrades cytosolic proteins into short peptides; the closed ends of the class I groove limit binding to peptides of about 8 to 10 amino acids.
3. Draw a doorway into the ER labeled TAP. TAP1 and TAP2 form an ATP-dependent transporter that moves peptides from the cytosol into the ER.
4. Inside the ER, draw MHC I: a heavy α chain with three domains (α1 and α2 form the groove) plus β2-microglobulin. Chaperones hold it until a peptide binds: calnexin first, then calreticulin, tapasin (which helps transfer peptides from TAP onto MHC I) and ERp57.
5. Arrow through the Golgi to the cell surface.
6. Draw a CD8+ T cell docking. Self peptide: ignored. Viral or tumor peptide: the T cell eliminates the cell.

Left-side summary: cytosolic protein → proteasome → TAP → ER (α chain + β2-microglobulin + peptide) → Golgi → surface → CD8.

Right side: MHC II, the outside pickup

1. Draw the APC engulfing a bacterium into an endosome, where the protein is digested into peptides.
2. Back in the ER, draw MHC II (an α and a β chain) with a plug in its groove: the invariant chain, which stops it from binding peptides inside the ER.
3. Arrow from the ER to an endosome. A protease cleaves most of the invariant chain, leaving a small fragment, CLIP (class II–associated invariant chain peptide), in the groove.
4. Fuse the two endosomes and draw HLA-DM pulling CLIP out and helping the exogenous peptide take its place.
5. Arrow to the cell surface.
6. Draw a CD4+ helper T cell recognizing the complex and releasing help, which ends in B-cell antibody production and an organized immune response.

Right-side summary: phagocytosis → endosome → MHC II arrives with invariant chain → CLIP → HLA-DM swaps CLIP for peptide → surface → CD4.

Optional step 7: add a dashed arrow from a dendritic cell's endosome to its MHC I (cross-presentation) and an NK cell beside a cell with no MHC I (missing self). Both are explained below.

MHC I vs MHC II at a glance

The class III region encodes inflammatory molecules (complement C2, C4 and factor B, TNF-α and lymphotoxin), not antigen-presenting molecules. All MHC genes are codominant, so every inherited allele is expressed.

Cross-presentation: exogenous antigen on MHC I

Cross-presentation is the process by which exogenous antigens captured by phagocytic antigen-presenting cells are processed and presented on MHC I. Dendritic cells do it (a subset marked by XCR1 is a key player). Why it matters:

• Viruses that do not infect dendritic cells, or that block direct presentation, can still prime CD8+ T cells, because the dendritic cell presents antigen it has eaten.
• Tumors can trigger CD8+ responses the same way.

On the exam, a dendritic cell that ingests virus-infected or tumor material and activates naive CD8+ T cells is cross-presenting; the class II route would activate CD4+ cells instead. The broader signal sequence (MHC plus costimulation) is in the T-cell activation mnemonic.

NK cells and "missing self"

Inhibitory receptors on NK cells recognize MHC class I, and NK cells can kill a target only when there is no strong inhibitory signal. Normal MHC I therefore protects healthy cells. Its absence suggests the cell is infected with a virus that downregulates MHC or has undergone malignant transformation with loss of MHC, and the NK cell kills it. Dropping MHC I to hide from CD8+ T cells therefore makes the cell an NK target. More in the NK cell Q-bank breakdown.

How viruses and tumors dodge MHC I

Each trick hides the cell from CD8+ T cells, but low surface MHC I also removes the brake on NK cells.

Bare lymphocyte syndromes

Type II is a combined immunodeficiency, so it belongs in your SCID-like differential (see SCID made easy).

HLA associations worth memorizing

Disease associations are from Merck's HLA chapter; drug alleles are from FDA labels. Type 1 diabetes: review books say DR3 and DR4, Merck's HLA chapter says DQ2 and DQ8; both are right, because these genes travel together as the DR3-DQ2 and DR4-DQ8 haplotypes, present in more than 90% of patients younger than 30 (Merck). Practice these in the HLA associations breakdown.

How USMLE tests it

• RBCs are anucleate, so they are the classic exception to "MHC I on all nucleated cells"; platelets do carry MHC I.
• β2-microglobulin is encoded on chromosome 15, not 6; both class II chains are on chromosome 6.
• Invariant chain = class II only. It blocks the class II groove in the ER; TAP and tapasin belong to class I.
• Langerhans cells are skin dendritic cells that express MHC II; they pick up haptens in allergic contact dermatitis.
• Transplant HLA typing looks at these same loci (A, B, C, DP, DQ, DR); see the transplant rejection breakdown.

Practice question

A virus encodes a protein that binds and inhibits TAP in the epithelial cells it infects. Which host response is most likely to kill these infected cells?

• A. CD8+ T cells recognizing viral peptides on the infected cells' MHC I
• B. CD4+ T cells recognizing viral peptides on the infected cells' MHC II
• C. NK cells that are no longer inhibited by MHC I on the infected cells
• D. Loading of viral peptides onto MHC I through the invariant chain pathway
• E. No cellular response, because exogenous antigen can never reach MHC I

Answer: C. Without TAP, peptides cannot enter the ER; MHC I chains are still made, but surface MHC I falls to abnormally low levels. Herpes simplex virus uses this exact trick. NK cells lose their inhibitory signal and kill the "missing self" cells.

• A: CD8+ T cells need peptide on MHC I, which is exactly what the virus has removed.
• B: epithelial cells are not professional APCs, and cytosolic viral proteins go to class I, not class II.
• D: the invariant chain is class II machinery; it plugs the class II groove and does nothing for class I.
• E: false twice: NK cells still respond, and dendritic cells can cross-present captured viral antigen on MHC I to prime CD8+ T cells.

Key takeaways

• Rule of 8: MHC I × CD8 = 8; MHC II × CD4 = 8.
• MHC I: HLA-A, -B, -C; all nucleated cells; cytosolic peptides via proteasome → TAP → ER; α chain + β2-microglobulin (chromosome 15).
• MHC II: HLA-DP, -DQ, -DR; professional APCs; endosomal peptides; invariant chain → CLIP → HLA-DM.
• Cross-presentation: dendritic cells put eaten antigen on MHC I to prime CD8+ T cells.
• Missing self: low MHC I (viral evasion, tumors) removes NK inhibition, and NK cells kill.
• Bare lymphocyte syndrome: type I = TAP defect (MHC I); type II = CIITA or RFX defect (MHC II).
• Must-know HLA links: B27 spondyloarthritis, DQ2/DQ8 celiac, B*57:01 abacavir, B*15:02 carbamazepine.

Sources

• Human Leukocyte Antigen (HLA) System — Merck Manual Professional Edition (2026)
• Cellular Components of the Immune System — Merck Manual Professional Edition (2026)
• Physiology, MHC Class I — StatPearls, NCBI Bookshelf (2022)
• Genetics, Histocompatibility Antigen — StatPearls, NCBI Bookshelf (2023)
• The generation of T-cell receptor ligands — Immunobiology, 5th ed., NCBI Bookshelf (2001)
• Cross-Presentation of Cell-Associated Antigens by MHC Class I in Dendritic Cell Subsets — Frontiers in Immunology (2015)
• Bare lymphocyte syndrome type I — MedlinePlus Genetics (2017)
• Bare lymphocyte syndrome type II — MedlinePlus Genetics (2017)
• Diabetes Mellitus (DM) — Merck Manual Professional Edition (2025)
• ZIAGEN (abacavir) prescribing information — DailyMed (2023)
• TEGRETOL (carbamazepine) prescribing information — DailyMed (2026)