Questions: Major Histocompatibility Complex Structure and Function

Question 1

A hepatocyte (liver cell) becomes infected by a virus. Can the adaptive immune system detect this infection, and if so, how?

• A. No — only professional antigen-presenting cells like dendritic cells can activate T cells, and hepatocytes are not APCs
• B. Yes — hepatocytes express MHC class I, which displays viral peptides from the cytoplasm to patrolling CD8+ cytotoxic T cells
• C. Yes — but only after the hepatocyte upregulates MHC class II to activate CD4+ helper T cells
• D. No — the liver degrades viral proteins via autophagy before they can be loaded onto MHC molecules

Answer: (B)

This question targets a key misconception: MHC class I is expressed on ALL nucleated cells, not just immune cells. Every nucleated cell in the body continuously samples its cytoplasmic proteins via the proteasome and loads the resulting peptides onto MHC-I. If a hepatocyte is infected, viral proteins are degraded in the cytoplasm, the peptides are loaded onto MHC-I, and the complex is displayed on the cell surface. CD8+ cytotoxic T cells recognize foreign peptide-MHC-I complexes and kill the infected cell. This is precisely why MHC-I is ubiquitous — every cell needs to be able to signal infection or transformation.

Question 2

What structural feature of MHC class II explains why it presents longer peptides (13–25 amino acids) than MHC class I (8–10 amino acids)?

• A. MHC class II molecules are physically larger and have a deeper binding groove
• B. MHC class II has an open-ended peptide-binding groove, while MHC class I has closed ends that constrain peptide length
• C. MHC class I uses disulfide bonds to clamp the peptide ends, while class II uses only non-covalent contacts
• D. MHC class II binds peptides covalently, allowing longer chains to be accommodated

Answer: (B)

In MHC class I, the peptide-binding groove is closed at both ends, with conserved residues that anchor the N- and C-termini of the peptide. This physically constrains the peptide length to 8–10 amino acids — shorter or longer peptides do not fit. MHC class II has an open groove with no end constraints, allowing peptides of 13–25 amino acids to extend beyond the groove ends. This structural difference directly reflects the different sources of peptides: cytoplasmic proteasomes generate shorter, more uniform fragments; endosomal proteases generate longer, more variable ones.

Question 3

MHC class I molecules display peptides derived from proteins synthesized inside the cell, allowing the immune system to detect viral infection or cancer even without any extracellular pathogen.

• T. True
• F. False

Answer: True

This is the fundamental purpose of MHC class I. Cells continuously degrade their own proteins via the proteasome (including viral proteins if infected, or mutant proteins if cancerous), and the resulting peptides are loaded onto MHC-I in the endoplasmic reticulum. The MHC-I–peptide complex is then displayed on the cell surface as a 'status report' of the cell's interior. CD8+ T cells patrol these displays; any foreign peptide triggers killing. This is how the immune system detects intracellular threats that antibodies and extracellular receptors cannot see.

Question 4

MHC polymorphism — the existence of thousands of HLA alleles in the human population — is a disadvantage for organ transplantation but serves no broader protective function for the species.

• T. True
• F. False

Answer: False

MHC polymorphism serves a critical population-level function: each allelic variant has a different peptide-binding groove, meaning different alleles present different subsets of pathogen-derived peptides. A pathogen that evolves peptides that escape one person's MHC alleles will still be presented by someone else's different alleles. This diversity ensures that no single pathogen strain can simultaneously evade immune recognition in the entire population. The transplantation problem is a side-effect of this adaptive diversity — donor MHC molecules look 'foreign' to the recipient's T cells, triggering rejection.

Question 5

Why does it make biological sense for MHC class I to be expressed on all nucleated cells rather than only on dedicated immune cells?

Model answer: Viruses and cancer mutations can occur in any cell type in the body — not just immune cells. If only immune cells expressed MHC-I, a virus infecting a hepatocyte, lung cell, or neuron would be invisible to CD8+ T cells; the infected cell could replicate virus indefinitely with no way to signal distress. By expressing MHC-I on every nucleated cell, the immune system gains continuous surveillance coverage across all tissues. Every cell becomes its own sentinel, displaying a sample of its intracellular protein environment. This turns every cell into a potential target for cytotoxic T cells if it is infected or transformed — a much more robust surveillance system than restricting it to dedicated immune cells.

The universality of MHC-I expression reflects the scope of the threat it guards against: intracellular pathogens and malignant transformation can happen anywhere in the body. The cost is the self-tolerance machinery required to prevent CD8+ T cells from killing healthy cells displaying normal self-peptides — an elaborate system of thymic selection and peripheral tolerance that is precisely what breaks down in some autoimmune diseases.