U01.02.008 Major histocompatibility complex I and II

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Learning Objectives

Master the structural and functional differences between MHC Class I and II. Understand their genetic loci (HLA), cellular expression, antigen loading pathways, and their specific roles in presenting endogenous versus exogenous antigens to T cells for the USMLE Step 1.

1. Genetic Loci and HLA Associations

The Major Histocompatibility Complex (MHC) is encoded by Human Leukocyte Antigen (HLA) genes.

Feature MHC Class I MHC Class II
Genetic Loci HLA-A, HLA-B, HLA-C(MHC I loci have 1 letter) HLA-DP, HLA-DQ, HLA-DR(MHC II loci have 2 letters)
Binding Partner TCR and CD8+(Rule of 8: 8 \times 1 = 8) TCR and CD4+(Rule of 8: $Latex  4 \times 2 = 8$)

2. Structure and Expression

The physical structure determines which T cell can dock with the complex.

Feature MHC Class I MHC Class II
Structure 1 long chain, 1 short chain (3\alpha, $Latex  1\beta_{2}$). 2 equal-length chains ($Latex  2\alpha$, $Latex  2\beta$).
Associated Protein \beta_{2}-microglobulin. Invariant chain.
Expression All nucleated cells, APCs, platelets (NOT RBCs). Only APCs (Dendritic cells, Macrophages, B cells).

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3. Antigen Processing and Loading

How the “garbage” of the cell is presented to the “police” (T cells) differs depending on the source of the antigen.

Feature MHC Class I MHC Class II
Antigen Source Endogenous (viral, cytosolic, or tumor proteins). Exogenous (bacterial or extracellular proteins).
Loading Site Loaded in the RER after delivery via TAP. Loaded in an acidified endosome after invariant chain release.
Function Signals to Cytotoxic T cells to kill the cell. Signals to Helper T cells to activate the immune response.

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High-Yield Clinical Pearls:

  • The RBC Exception: RBCs are NOT nucleated; therefore, they do not express MHC I. This is why they cannot be infected by viruses that require MHC I presentation to be “seen,” but also why they are prone to certain parasitic infections like Malaria.
  • TAP Deficiency: A defect in the TAP transporter leads to a failure of MHC I expression, resulting in a lack of CD8+ T cell response.
  • Invariant Chain: Its primary job is to “clog” the MHC II groove in the RER to prevent endogenous proteins from binding to it accidentally. It only leaves once the complex reaches the endosome.

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