MHC and antigen presentation

Concept

MHC and antigen presentation

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Statement

Displaying cellular contents to T cells.

Why it matters

innate-adaptive-immunity establishes that adaptive immunity depends on T cells recognising specific threats, but a T cell cannot itself enter a cell to inspect its contents for infection or malignancy; MHC and antigen presentation is the mechanism that solves this by having every cell continuously display fragments of its own internal proteins on its surface, turning an otherwise invisible intracellular problem into something a patrolling T cell can actually see. clonal-selection then depends entirely on this display: a T cell can only be activated by an antigen it can physically encounter, and presentation is what brings intracellular antigen out to where a T cell's receptor can reach it.

The distinction between MHC class I and class II presentation is also what separates the two branches of cell-mediated immunity — killing infected cells outright versus coordinating other immune cells — so understanding presentation is a prerequisite for understanding why cytotoxic and helper T cells do fundamentally different jobs.

Hypotheses

Nearly every nucleated cell in the body expresses MHC class I molecules constitutively.This universality is what allows any infected or transformed cell, anywhere in the body, to be surveilled — if only specialised cells displayed class I, a pathogen or tumour arising in an unmonitored cell type would be effectively invisible to cytotoxic T cells. MHC molecules bind peptide fragments, not intact proteins, and display them non-covalently in a surface groove.Only a short linear peptide (roughly 8–10 residues for class I, somewhat longer for class II) fits the MHC binding groove; intact folded proteins are far too large, which is exactly why antigen must first be proteolytically processed into fragments before it can be displayed at all. MHC genes are the most polymorphic loci known in the human genome, with many alleles per locus across a population; this diversity is a population-level defence against pathogens evolving to evade presentation by any single, fixed peptide-binding specificity, at the cost of making organ transplantation between unrelated individuals immunologically difficult.

Proof

\text{Class I pathway: cytosolic protein} \to \text{proteasome degradation} \to \text{TAP transport into ER} \to \text{loading onto MHC I} \to \text{surface display}

Proteins synthesised in the cytosol (including viral proteins made by an infected cell's own ribosomes, or mutant proteins from a cancer cell) are continuously degraded by the proteasome; resulting peptides are actively transported into the endoplasmic reticulum, where they load onto newly assembled MHC class I molecules before the complex reaches the cell surface. A

\text{Class II pathway: extracellular/vesicular protein} \to \text{lysosomal degradation} \to \text{loading onto MHC II in the endosome} \to \text{surface display}

Specialised antigen-presenting cells (dendritic cells, macrophages, B cells) internalise extracellular material by phagocytosis or endocytosis; this material is degraded within lysosomes and loaded onto MHC class II molecules trafficking through the same endosomal compartment, which then move to the surface. A

\text{Cytotoxic T cells (CD8}^+\text{) recognise MHC I}+\text{peptide; helper T cells (CD4}^+\text{) recognise MHC II}+\text{peptide.}

The CD8 and CD4 co-receptors bind MHC class I and class II respectively, restricting each T cell subtype to surveying only the pathway matched to its co-receptor; this is why the two presentation routes of Steps 1–2 map onto two functionally distinct T cell responses. A

\text{Peptide displayed on class I} \Rightarrow \text{signals the cell's own internal state (infected/transformed vs healthy).}

Because class I samples the cytosolic proteome continuously (Step 1), a cell producing viral or mutant proteins internally will unavoidably display fragments of them, even though those proteins never leave the cell — presentation converts an otherwise hidden internal defect into an externally visible marker. A

\text{Peptide displayed on class II} \Rightarrow \text{signals material an antigen-presenting cell has sampled from its surroundings.}

Class II presentation (Step 2) reports on the extracellular environment an antigen-presenting cell has encountered, not on that cell's own internal state, which is why class II activation of helper T cells coordinates a broader immune response rather than triggering direct killing of the presenting cell itself. A

Result

\text{MHC I}+\text{peptide}\ \xrightarrow{\text{CD8}^+}\ \text{cytotoxic response} \qquad \text{MHC II}+\text{peptide}\ \xrightarrow{\text{CD4}^+}\ \text{helper response}

Reading. Two parallel presentation pathways, sampling two different compartments (cytosol versus endosome/phagosome) and reporting to two different T cell subsets, together let the adaptive immune system distinguish "this cell is compromised internally" from "this cell has encountered a threat externally."

Scope. Both pathways depend on functional proteasome, TAP transporter, and lysosomal machinery respectively; several viral immune-evasion strategies specifically target these steps (Discussion).

Corollaries & converses

immunological-memory depends on antigen presentation having occurred correctly during the primary response: memory T cells are selected from those originally activated by properly presented peptide-MHC complexes.
antibody-diversity's B cell receptors recognise intact, unprocessed antigen directly, unlike T cell receptors, which strictly require peptide already loaded onto MHC (Step 3) — a fundamental mechanistic difference between the two arms of adaptive recognition.
Converse: a cell displaying no unusual peptides on MHC I, despite being infected, can evade cytotoxic detection entirely — several viruses exploit exactly this route (Fails without), which is why NK cells provide a backup surveillance mechanism specifically for MHC-I-low cells.

Fails without

Lose MHC class I expression (Hypotheses): a cell that downregulates class I — a strategy several viruses (e.g. herpesviruses) actively employ — becomes invisible to cytotoxic T cell surveillance regardless of how much viral protein it is actually producing internally, since Step 1's entire pathway has nothing to display on; only innate natural-killer-cell surveillance, which specifically responds to abnormally low MHC I, catches this evasion route.
Fail to process protein into short linear peptides (Hypotheses' groove-binding requirement): an intact, folded protein cannot physically load into the MHC binding groove, so any material a pathogen manages to keep from proteolytic processing (some pathogens actively block proteasome or lysosomal degradation) is never displayed at all, regardless of how abundant it is within the cell.

Common errors

Assuming MHC class II is expressed by all cells like class I; it is normally restricted to professional antigen-presenting cells (dendritic cells, macrophages, B cells).
Confusing which T cell subset pairs with which MHC class — CD8/class I/cytotoxic and CD4/class II/helper is a fixed pairing (Step 3), not an arbitrary or interchangeable one.
Believing MHC molecules themselves are the antigen; the antigen is the bound peptide, and MHC is simply the fixed, self-encoded scaffold that displays it.
Assuming antigen presentation implies the presenting cell is itself infected; a healthy dendritic cell that has phagocytosed pathogen debris presents via class II (Step 2) without being infected at all.

Discussion

MHC molecules were first identified through their role in transplant rejection — the "major histocompatibility complex" name itself reflects this original discovery context, well before their actual physiological function in antigen presentation was understood; the human version of this gene complex is called HLA (human leukocyte antigen).

MHC's extraordinary population-level polymorphism (Hypotheses) means any two unrelated individuals almost always carry different MHC alleles, which is the direct molecular reason organ and tissue transplants between unrelated donors require immunosuppression or careful HLA matching — the recipient's T cells can directly recognise a mismatched donor's MHC molecules themselves as foreign, a rapid rejection route distinct from ordinary peptide-specific recognition.

Common misconception: that antigen presentation only matters during active infection. Every nucleated cell presents self-peptides on class I continuously, even when perfectly healthy; this baseline self-presentation is what allows the immune system to distinguish an abnormal (foreign or mutant) peptide from the enormous background of normal self peptide being displayed at all times, a comparison central to how self/non-self discrimination actually operates.

Worked examples

\text{A cell infected by influenza synthesises viral nucleoprotein in its cytosol.}

Some newly made viral nucleoprotein is degraded by the proteasome alongside the cell's own proteins (Step 1); resulting viral peptide fragments are transported into the ER by TAP and loaded onto MHC class I molecules, which then traffic to the cell surface exactly as any self-peptide would. A

\text{Surface MHC I}+\text{viral peptide is recognised by a circulating CD8}^+\text{ T cell bearing a matching receptor.}

Because this particular peptide-MHC combination did not exist before infection, a CD8⁺ T cell specific to it (selected and expanded via clonal-selection) is activated on contact and triggers direct killing of the infected cell, exactly as Step 3–4 predicts. A

\text{Internal infection} \to \text{class I display} \to \text{cytotoxic killing of the infected cell itself}

Reading. The infected cell is destroyed specifically because its own class I presentation exposed an internal problem it could not otherwise hide.

Scope. The identical logic underlies cytotoxic surveillance of tumour cells presenting mutant self-peptides.

Problems

A tumour cell downregulates MHC class I expression to avoid cytotoxic T cell recognition. Explain, using the Fails without discussion, why this strategy does not make the cell completely invisible to the immune system.
Solution
Abnormally low MHC I expression is itself detected by natural killer cells, which are inhibited by normal MHC I levels and activated when that inhibitory signal is missing (Fails without, first bullet). By downregulating class I to escape cytotoxic T cells, the tumour cell becomes a target for NK-cell-mediated killing instead, so the evasion strategy trades one surveillance route for vulnerability to another.
A dendritic cell phagocytoses bacteria from the extracellular environment but is not itself infected. Which MHC class will it use to present bacterial antigen, and to which T cell subset?
Solution
Extracellular material taken up by phagocytosis is processed through the lysosomal/endosomal route (Step 2) and loaded onto MHC class II, which presents to CD4⁺ helper T cells (Step 3) — not MHC class I, since the bacterial protein never enters the cytosolic proteasome pathway.
Explain why a peptide from a normal, abundant self-protein and a peptide from a rare mutant self-protein can both appear on the same cell's MHC class I, and what distinguishes a "safe" self-peptide from one that triggers a T cell response.
Solution
MHC class I samples the entire cytosolic proteome essentially indiscriminately (Step 1), so both normal and mutant proteins are degraded and displayed without distinction at the loading step itself. What determines whether a given peptide-MHC complex triggers a response is whether any T cell bearing a matching receptor has survived central tolerance mechanisms during development; T cells reactive to normal self-peptides are eliminated or suppressed, while a genuinely novel mutant peptide may be recognised by a T cell that was never selected against it.