Learning Objective: By the end of this topic, medical students should be able to differentiate between MHC class I and class II molecules, including their structure, expression, function, and antigen processing mechanisms, and apply this understanding to clinical immunology scenarios on the USMLE Step 1.

The Major Histocompatibility Complex (MHC) is a set of genes located on chromosome 6 that encode cell surface glycoproteins responsible for antigen presentation to T cells.
In humans, these genes are referred to as Human Leukocyte Antigen (HLA) genes.

MHC Class I vs. Class II: Key Comparison Table

Mechanism of Antigen Presentation

MHC Class I Pathway (Endogenous)

• Viral or cytosolic proteins → degraded in proteasome
• Peptides transported via TAP into RER
• Loaded onto MHC I → presented on cell surface
• Recognized by CD8⁺ cytotoxic T cells

MHC Class II Pathway (Exogenous)

• Extracellular proteins → phagocytosed by APCs
• Fusion with lysosome → peptide fragments
• MHC II with invariant chain moves to endosome
• Invariant chain removed, peptide loaded
• Presented to CD4⁺ helper T cells

Key Points for USMLE Step 1

• Only nucleated cells express MHC I — RBCs do not.
• MHC II is restricted to APCs.
• CD8 → cytotoxic, CD4 → helper mnemonic helps link MHC type to T-cell type.
• β₂-microglobulin is important for MHC I stability (mutations → immunodeficiency).
• Invariant chain prevents premature peptide loading on MHC II in the ER.

Clinical Correlations