Step by Step
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 signals determines whether the NK cell kills or stands down.
MS
Missing Self — why an absent MHC I is itself a red flag
Many viruses downregulate MHC class I on infected cells specifically to hide from CD8+ Cytotoxic T cells, which require MHC I to recognize infected cells. But this evasion strategy backfires — an NK cell's inhibitory KIR receptor no longer detects MHC I, removes the 'stand down' signal, and the NK cell kills the cell precisely because it's missing something that should 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 at once.
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, granzymes trigger apoptosis. The key difference is what triggers the kill: NK cells respond to missing/altered self and don't require prior sensitization, while CD8+ T cells require prior antigen exposure and MHC I presentation.
+
Enhancement — cytokines that boost NK activity
NK cell activity is enhanced by IL-2, IL-12, and interferons — meaning during a viral infection (when interferon production is already high), NK cell killing gets amplified as part of the broader innate antiviral response.
Applied Walkthrough
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A tumor cell downregulates MHC class I as a strategy to evade recognition by CD8+ Cytotoxic T cells.
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Ask: does this evasion strategy actually work? Only partially — while it does hide the tumor cell from CD8+ T cells (which require MHC I to recognize a target), 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.
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Contrast: if the tumor cell instead kept normal MHC I expression but displayed abnormal tumor antigens, 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.
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This dual-layer surveillance — CD8+ T cells watching for abnormal antigen on MHC I, NK cells watching for the absence of MHC I altogether — means a cell can't successfully evade both systems using the same trick.
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.
⚠ Common Trap
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. The distinguishing detail is the trigger: CD8+ cells need to see MHC I displaying a specific abnormal antigen (adaptive, sensitized), while NK cells respond to the absence of MHC I altogether (innate, no sensitization required).
✓ Quick Self-Check
1. What two types of receptors do NK cells carry, and what does each detect?
Activating receptors (like NKG2D, detecting stress ligands) and inhibitory receptors (like KIR, checking for MHC I presence).
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2. What is the 'missing self' hypothesis?
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.
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3. Why do virus-infected cells that downregulate MHC I become vulnerable to NK cells?
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.
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4. How do NK cells kill their targets once activated?
Via perforin (creating pores) and granzymes (triggering apoptosis) — the same mechanism used by CD8+ Cytotoxic T cells.
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5. What is the key functional difference between NK cells and CD8+ T cells?
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).
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