Questions: MHC Class II Antigen Presentation Pathway

Question 1

A macrophage phagocytoses a bacterium. Which sequence of events correctly describes how a bacterial protein ultimately activates a CD4+ T cell?

• A. The bacterial protein is degraded by the proteasome and its peptides are loaded onto MHC-I molecules in the ER, then displayed to CD4+ T cells
• B. The bacterial protein is degraded by lysosomal cathepsin proteases into peptides that load onto MHC-II molecules in the endosomal compartment, then displayed to CD4+ T cells
• C. The intact bacterial protein is displayed directly on the macrophage surface for direct recognition by CD4+ T cell receptors
• D. The bacterial protein is degraded in the ER and loaded onto MHC-II before the complex is targeted to the endosome for final processing

Answer: (B)

MHC-II presents exogenous (extracellular-origin) antigens to CD4+ T cells via the endosomal pathway. Endocytosed bacteria are degraded in progressively acidifying endosomes by cathepsin proteases (not the proteasome, which handles endogenous proteins for MHC-I). The resulting peptides are loaded onto MHC-II in the endosomal compartment (not the ER), and the complex traffics to the cell surface. MHC-I presents endogenous peptides (from proteins made inside the cell) to CD8+ cytotoxic T cells — a completely separate pathway.

Question 2

The invariant chain (Ii) serves two essential functions in the MHC-II antigen presentation pathway. It:

• A. Degrades CLIP in the endosome and directly loads high-affinity antigenic peptides onto MHC-II
• B. Blocks the MHC-II peptide-binding groove to prevent premature peptide loading in the ER, and acts as a targeting signal directing the MHC-II complex from the ER through the Golgi to the endosomal compartment
• C. Activates cathepsin proteases in early endosomes to initiate antigen degradation
• D. Prevents MHC-II from associating with HLA-DM before reaching the appropriate endosomal compartment

Answer: (B)

The invariant chain (Ii) solves two problems simultaneously. First, the ER contains many self-peptides and partially folded proteins that would load promiscuously into the empty MHC-II groove — Ii blocks this by physically occupying the groove. Second, Ii contains a targeting sequence in its cytoplasmic tail that routes the MHC-II/Ii complex from the ER through the Golgi to the endosomal compartment where antigen degradation is occurring. CLIP removal (by HLA-DM) and peptide loading are subsequent steps, performed by different molecules.

Question 3

HLA-DM catalyzes the removal of CLIP from the MHC-II peptide-binding groove and facilitates loading of high-affinity antigenic peptides, functioning as a peptide editor in the endosomal compartment.

• T. True
• F. False

Answer: True

Correct. After cathepsin S degrades most of the invariant chain in the endosome, a small fragment called CLIP (class II-associated invariant chain peptide) remains lodged in the MHC-II groove. HLA-DM — a non-classical MHC-II molecule that does not itself present peptides — binds the MHC-II/CLIP complex, destabilizes the CLIP interaction, and catalyzes exchange for the highest-affinity antigenic peptide available in the endosome. This editing function ensures that MHC-II displays the most stable peptide-MHC complexes, enriching the surface display for immunologically relevant peptides.

Question 4

MHC class II molecules present peptides derived from proteins synthesized inside the presenting cell (endogenous antigens) to CD4+ helper T cells.

• T. True
• F. False

Answer: False

This describes the MHC class I pathway, not MHC class II. MHC-I presents endogenous antigens (proteins made inside the cell, degraded by the proteasome, transported into the ER by TAP, and loaded in the ER) to CD8+ cytotoxic T cells. MHC-II presents exogenous antigens (proteins captured from outside the cell by endocytosis, degraded by lysosomal cathepsins in acidified endosomes, and loaded in the endosomal compartment) to CD4+ helper T cells. The two pathways are separately regulated and serve distinct immunological functions.

Question 5

Why is it essential that the invariant chain blocks the MHC-II peptide-binding groove in the ER, and what would happen without this protection?

Model answer: Without the invariant chain, the empty MHC-II groove in the ER would be accessible to self-peptides and other ER-resident peptides generated during normal protein processing. These peptides would load into the groove and be displayed on the cell surface — potentially triggering T cell responses against self-antigens (autoimmunity) or presenting irrelevant peptides that crowd out immunologically relevant ones.

The invariant chain is a solution to the problem of specificity in antigen presentation: MHC-II should display peptides from exogenous antigens sampled in the endosome, not from proteins in the ER. By physically occupying the groove until the molecule reaches the appropriate acidic endosomal compartment, Ii ensures that the groove is only 'open for business' in the right place (endosome) at the right time (after cathepsin-mediated Ii degradation). HLA-DM then further enforces quality control by selecting for high-affinity peptide-MHC interactions.