Before We Start
A virus's evasion trick becomes its own downfall
Many viruses hide from CD8+ T cells by removing MHC class I from an infected cell's surface, since CD8+ cells need MHC I to recognize a target at all. But that same missing MHC I is exactly what triggers an NK cell to kill — the evasion strategy backfires against a different arm of the immune system.
💡 Memory Trick
NK cells kill cells that LACK MHC I — "missing self." No prior sensitization needed. A cell can't hide from both CD8+ T cells and NK cells using the same trick, since each one is looking for the opposite thing.
The Key Points
Two receptor types, the missing-self trigger, and the kill mechanism
2R
Two receptor types — activating and inhibitory signals compete
NK cells carry both activating receptors (like NKG2D, which detects stress ligands on abnormal cells) and inhibitory receptors (like KIR, which specifically checks for the presence of MHC class I). The balance between these two competing signals determines whether the NK cell ultimately kills or stands down.
🦠 An NK cell encountering a cell with both stress ligands (activating signal) and normal MHC I (inhibitory signal) weighs both inputs — the inhibitory MHC I signal normally wins out, telling the NK cell to stand down.
MS
Missing self — why an absent MHC I is itself the red flag
Many viruses downregulate MHC class I on infected cells specifically to hide from CD8+ Cytotoxic T cells, which absolutely require MHC I to recognize an infected cell at all. But this evasion strategy backfires: an NK cell's inhibitory KIR receptor no longer detects MHC I, removing the "stand down" signal entirely, and the NK cell kills the cell precisely because it's missing something that should normally be there.
🦠 A cell infected with a herpesvirus downregulates MHC I to evade CD8+ T cells, but this exposes it to NK cell killing instead — the virus can't hide from both arms of the immune system using the same single trick.
Kill
The kill mechanism — same tools as CD8+ cells, different trigger logic
Once activated, NK cells use the same perforin and granzyme mechanism as CD8+ Cytotoxic T cells — perforin creates pores in the target cell membrane, granzymes trigger apoptosis inside it. The key difference is what triggers the kill: NK cells respond to missing or altered self and require no prior sensitization at all, while CD8+ T cells require prior antigen exposure and active MHC I presentation.
🦠 An NK cell and a CD8+ T cell can both kill the exact same infected cell using identical tools (perforin, granzymes) — but they arrive at that kill decision through completely opposite logic.
+
Enhancement — cytokines that boost NK activity
NK cell activity is enhanced by IL-2, IL-12, and interferons — meaning during an active viral infection, when interferon production is already elevated as part of the innate antiviral response, NK cell killing gets amplified right alongside it.
🦠 During an active viral infection, the already-elevated interferon levels don't just warn neighboring cells (as covered in the Interferons lesson) — they also directly amplify NK cell killing activity as part of the same coordinated innate response.
🏥 Applied Scenario
A tumor cell downregulates MHC class I as a strategy to evade recognition by CD8+ Cytotoxic T cells.
Step 1
Assess whether the strategy actually works: Does this evasion strategy actually succeed? Only partially — while it does hide the tumor cell from CD8+ T cells (which require MHC I to recognize a target at all), it exposes the tumor cell to NK cells instead, since the absence of MHC I removes the inhibitory signal that would normally tell an NK cell to stand down.
Step 2
Contrast with a different evasion approach: If the tumor cell instead kept normal MHC I expression but displayed abnormal tumor antigens on it, CD8+ T cells would be the ones to recognize and kill it — NK cells wouldn't be specifically triggered by MHC I in that case, since the inhibitory signal is still present and intact.
Step 3
Recognize the dual-layer surveillance this creates: This dual-layer surveillance — CD8+ T cells watching for abnormal antigen displayed on MHC I, NK cells watching for the absence of MHC I altogether — means a cell genuinely cannot successfully evade both systems using the same single trick.
Step 4
Conclusion: A tumor or virus faces a real dilemma: keep MHC I and risk CD8+ recognition, or remove it and risk NK recognition instead — there's no single evasion move that defeats both arms at once.
📌 Exam Application
Exams test the "missing self" concept specifically — that NK cells are triggered by the ABSENCE of MHC I, not its presence. They also test that NK cells, unlike CD8+ T cells, require no prior sensitization (making them part of innate rather than adaptive immunity), and the cytokines (IL-2, IL-12, interferons) that enhance their activity.
⚠️ The Trap — Confusing NK Cells With CD8+ Cytotoxic T Cells
The most common trap is confusing NK cells with CD8+ Cytotoxic T cells, since both kill via perforin/granzymes and both target virus-infected or tumor cells using identical tools. The distinguishing detail is the trigger logic: CD8+ cells need to see MHC I actively displaying a specific abnormal antigen (adaptive, requires prior sensitization), while NK cells respond to the ABSENCE of MHC I altogether (innate, no sensitization required at all).
✓ Quick Self-Test
Answer before checking:
1. What two types of receptors do NK cells carry, and what does each detect?
2. What is the "missing self" hypothesis?
3. Why do virus-infected cells that downregulate MHC I become vulnerable to NK cells?
4. How do NK cells kill their targets once activated?
5. What is the key functional difference between NK cells and CD8+ T cells?
Answers:
1. Activating receptors (like NKG2D, detecting stress ligands) and inhibitory receptors (like KIR, checking for MHC I presence).
2. NK cells kill cells that lack MHC class I, since the absence of MHC I removes the inhibitory signal that would normally tell the NK cell to stand down.
3. Downregulating MHC I helps the cell evade CD8+ T cells, but it also removes the inhibitory signal for NK cells, exposing the cell to NK-mediated killing instead.
4. Via perforin (creating pores) and granzymes (triggering apoptosis) — the same mechanism used by CD8+ Cytotoxic T cells.
5. NK cells require no prior sensitization and respond to missing/altered self (innate); CD8+ T cells require prior antigen exposure and MHC I presentation of a specific antigen (adaptive).