Step 1 topics → Immunology → MHC Class I and II

MHC Class I and II

USMLE Step 1 trap: Confuses MHC I expression as restricted to APCs rather than all nucleated cells. MHC class I is expressed on all nucleated cells in the body, allowing CD8+ CTLs to survey every cell for intracellular pathogens.

MHC class I and II are the molecular display systems that let T cells know what's happening inside (and outside) cells, and USMLE Step 1 loves this topic because it sits at the intersection of mechanism and clinical correlation. Class I presents endogenous peptides to CD8+ cytotoxic T cells; class II presents exogenous peptides to CD4+ helper T cells — you need to know the loading pathways, which T cell binds which class, and which HLA alleles are linked to specific diseases.

The exam tests this from multiple angles: straight recall (which cell types express MHC I vs II), mechanism (how endogenous vs exogenous antigens get loaded), and clinical application (a patient with uveitis and back pain — which HLA? A drug hypersensitivity reaction — which allele?). Passage-based questions will often describe a disease presentation and ask you to identify the relevant HLA association, or describe an immune process and ask you to identify which MHC pathway is involved.

The tricky parts are consistent. Students flip CD4/CD8 with MHC II/I, assume MHC I is restricted to APCs like MHC II is, and mix up the HLA-disease pairs — especially HLA-B27 (spondyloarthropathies, not RA) and the DR4/DR3 split. USMLE Step 1 also tests HLA-B57:01 for abacavir hypersensitivity and HLA-B*1502 for carbamazepine-induced Stevens-Johnson syndrome, so these pharmacogenomic associations are fair game alongside the classic autoimmune pairings.

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Common misconceptions

Common mistake
Wrong: MHC class I is expressed only on professional antigen-presenting cells like dendritic cells and macrophages.
Right: MHC class I is expressed on all nucleated cells in the body, allowing CD8+ CTLs to survey every cell for intracellular pathogens.
MHC class I needs to be on every nucleated cell — not just APCs — because CD8+ CTLs are constantly patrolling for infected or malignant cells anywhere in the body. If MHC I were restricted to APCs, a virus replicating inside a hepatocyte or a mutation in a skin keratinocyte would be invisible to cytotoxic T cells. Professional APCs (dendritic cells, macrophages, B cells) are distinguished by their expression of MHC class II, not by exclusive expression of MHC I.
Common mistake
Wrong: CD4+ T cells recognize antigen on MHC class I and CD8+ T cells recognize antigen on MHC class II.
Right: CD4+ T cells recognize antigen presented on MHC class II; CD8+ T cells recognize antigen on MHC class I — the number of the MHC class matches the CD number of the T cell.
Use the number match as a memory anchor: CD4 pairs with MHC class II (4 × 2 = 8, or simply '4 goes with II'). CD4+ helper T cells respond to exogenous antigens processed by APCs and presented on MHC II; CD8+ cytotoxic T cells respond to endogenous antigens (viral proteins, tumor antigens) presented on MHC I. Flipping this pair is one of the most common errors on USMLE Step 1 immune questions, and it cascades into wrong answers about which cells are killed and which are helped.
Common mistake
Wrong: Cross-presentation is used to activate CD4+ helper T cells against extracellular antigens.
Right: Cross-presentation allows dendritic cells to load exogenous antigens onto MHC class I to prime naive CD8+ CTLs against pathogens that do not directly infect APCs (e.g., viruses infecting non-APCs, tumor cells).
Cross-presentation solves a specific problem: how do you prime CD8+ CTLs against a virus that infects muscle cells or a tumor that isn't an APC? The answer is that dendritic cells engulf debris from those cells and use a specialized pathway to load those exogenous peptides onto MHC I instead of MHC II. The result is activation of naive CD8+ CTLs. CD4+ T cells are activated by the normal exogenous pathway (antigen → lysosome → MHC II) and do not require cross-presentation.
Common mistake
Wrong: HLA-B27 is associated with rheumatoid arthritis.
Right: HLA-B27 is associated with seronegative spondyloarthropathies (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, IBD-associated arthritis); rheumatoid arthritis is associated with HLA-DR4.
HLA-B27 is a class I allele linked to the seronegative spondyloarthropathies — ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and IBD-associated arthritis. Rheumatoid arthritis is a class II disease associated with HLA-DR4. The confusion likely arises because both involve joints, but the seronegativity (absent rheumatoid factor) and axial/entheseal involvement are the clinical clues that point to B27, not DR4.
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What the exam tests

  1. Know which cell types express MHC class I (all nucleated cells) versus MHC class II (professional APCs: dendritic cells, macrophages, B cells), and which T cell subset — CD8+ or CD4+ — is activated by each class.
  2. Understand the two antigen loading pathways: endogenous proteins are degraded by the proteasome and loaded onto MHC I in the ER; exogenous proteins are taken up by phagocytosis/endocytosis, degraded in lysosomes, and loaded onto MHC II.
  3. Explain why cross-presentation exists and what it accomplishes: dendritic cells reroute exogenous antigens onto MHC I to prime naive CD8+ CTLs against pathogens or tumors that don't directly infect APCs.
  4. Match the classic HLA alleles to their associated diseases: HLA-B27 with seronegative spondyloarthropathies, HLA-DR4 with rheumatoid arthritis, HLA-DR3/DR4 with type 1 diabetes, HLA-DR3 with lupus and Graves disease, HLA-DQ2/DQ8 with celiac disease, HLA-B57:01 with abacavir hypersensitivity, and HLA-B*1502 with carbamazepine-induced SJS.

Can you avoid these mistakes?

A patient with HIV has a CD4+ T cell count of 50 cells/µL. A dendritic cell in the lymph node is presenting an HIV-derived peptide to a naive T cell. Which MHC class is being used, and what is the T cell receptor coreceptor on the responding T cell?
A research experiment infects hepatocytes (liver parenchymal cells) with a novel virus. Which MHC class will present viral peptides on the surface of infected hepatocytes, and which T cell subset will recognize and destroy them?
A 28-year-old man presents with low back pain that improves with exercise, bilateral sacroiliitis on MRI, and anterior uveitis. Which HLA allele is most associated with his condition, and how does it differ from the HLA allele associated with rheumatoid arthritis?
A dendritic cell engulfs a tumor cell fragment from a melanoma that does not directly infect the dendritic cell. Describe the mechanism by which this leads to activation of CD8+ cytotoxic T lymphocytes, and name the process.

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