Step by Step
1
MHC class I — presents to CD8+ cells
Expressed on ALL nucleated cells, MHC class I presents intracellular peptides (like viral or tumor proteins) to CD8+ cytotoxic T cells, leading to the target cell being killed. Memory trick: MHC I × CD8 = 8.
2
MHC class II — presents to CD4+ cells
Expressed only on professional antigen-presenting cells (dendritic cells, macrophages, B cells), MHC class II presents extracellular peptides to CD4+ helper T cells, activating a broader immune response. Memory trick: MHC II × CD4 = 8 as well.
3
The two-signal rule for T cell activation
T cell activation requires two separate signals. Signal 1 is the T cell receptor (TCR) binding the MHC-peptide complex. Signal 2 (costimulation) is CD28 on the T cell binding B7 on the antigen-presenting cell. Signal 1 alone, without Signal 2, produces anergy — T cell unresponsiveness — rather than activation.
4
Why the two-signal rule matters, and a clinical application
This two-signal requirement helps prevent autoimmune reactions to self-antigens, since accidental TCR-MHC binding alone won't trigger a full immune response. CTLA-4 competes with CD28 for B7 binding, acting as an immune checkpoint — this checkpoint is specifically exploited (blocked) in certain cancer immunotherapies to boost anti-tumor immune responses.
Applied Walkthrough
1
A virus-infected cell displays viral peptide fragments on MHC class I (since MHC I is expressed on all nucleated cells) — this is recognized by a CD8+ cytotoxic T cell, which then kills the infected cell directly.
2
Meanwhile, a dendritic cell that has engulfed extracellular bacteria displays bacterial peptide fragments on MHC class II — but only because dendritic cells are professional antigen-presenting cells with MHC II available. This is recognized by a CD4+ helper T cell, activating a broader immune response.
3
For either T cell to actually become activated (rather than anergic), a second signal is required: CD28 on the T cell must also bind B7 on the presenting cell — TCR-MHC binding alone (Signal 1) isn't sufficient.
4
In cancer immunotherapy, drugs that block CTLA-4 prevent it from competing with CD28 for B7 binding — effectively removing a brake on T cell activation and boosting the immune system's ability to attack tumor cells.
Exam Application
Exams test whether you can correctly match MHC class I to CD8+ cells and MHC class II to CD4+ cells (using the ×8 memory trick), and whether you understand the two-signal requirement for T cell activation, including what happens with Signal 1 alone (anergy).
⚠ Common Trap
The most common trap is mixing up which MHC class pairs with which CD marker — remember the memory trick: MHC I × CD8 = 8, and MHC II × CD4 = 8 — both products equal 8, helping keep the correct pairing straight.
✓ Quick Self-Check
1. What does MHC class I present, to which cells, and on which cell types is it expressed?
Intracellular peptides, to CD8+ cytotoxic T cells; expressed on all nucleated cells.
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2. What does MHC class II present, to which cells, and on which cell types is it expressed?
Extracellular peptides, to CD4+ helper T cells; expressed only on professional antigen-presenting cells.
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3. What are Signal 1 and Signal 2 in T cell activation?
Signal 1 is TCR binding the MHC-peptide complex; Signal 2 is CD28 (on the T cell) binding B7 (on the APC).
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4. What happens if a T cell receives Signal 1 without Signal 2?
Anergy — the T cell becomes unresponsive rather than activated.
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5. What is CTLA-4, and how is it exploited in cancer treatment?
An immune checkpoint that competes with CD28 for B7 binding; blocking CTLA-4 removes this brake, boosting anti-tumor immune responses.
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