Questions: Natural Killer Cells and Innate Lymphoid Cells

Question 1

A tumor cell has evolved to completely downregulate MHC class I expression in order to evade CD8+ cytotoxic T cells. What is the most likely consequence for NK cell activity against this tumor?

• A. NK activity decreases because NK cells require MHC-I recognition to identify targets
• B. NK activity increases because loss of MHC-I removes the inhibitory signal that normally prevents NK cell killing
• C. NK activity is unchanged because NK cells only respond to foreign antigens presented by MHC-I
• D. NK activity depends entirely on whether the tumor also upregulates stress ligands like MICA

Answer: (B)

This is the missing self hypothesis in action. NK inhibitory receptors (KIRs in humans) bind MHC-I on healthy cells and send 'do not kill' signals. When a tumor downregulates MHC-I to hide from CD8+ T cells, it inadvertently removes these inhibitory signals — the NK cell is no longer told to stand down, and the balance shifts toward killing. This is why NK cells and cytotoxic T cells form a complementary surveillance system: what one escapes, the other catches.

Question 2

Once an NK cell's activation threshold is crossed, by what mechanism does it kill the target cell?

• A. It secretes antibodies that opsonize the target for phagocytosis by macrophages
• B. It presents target antigens on MHC-II to recruit helper T cells
• C. It releases cytokines that induce apoptosis through receptor-mediated signaling
• D. It exocytoses granules containing perforin and granzymes, which form pores and activate the caspase cascade in the target cell

Answer: (D)

NK cells use the same granule-based cytotoxic machinery as CD8+ T cells. Perforin polymerizes in the target cell membrane to form pores; granzymes enter through these pores and activate caspases, triggering apoptosis. This mechanism is efficient, directional (granules are released toward the target), and lethal within minutes. The NK cell itself is not harmed because its own granule proteins require the right pH and membrane conditions to activate — the same reason cytotoxic T cells are not self-lethal.

Question 3

NK cells require prior exposure to a specific pathogen or tumor antigen before they can become activated and kill infected cells — like cytotoxic T cells, they depend on adaptive immune priming.

• T. True
• F. False

Answer: False

NK cells are innate effectors: they respond within hours of infection without prior sensitization, using germline-encoded receptors (not somatically rearranged ones). Cytotoxic T cells, by contrast, require days of activation, proliferation, and differentiation before they can kill. This is the whole point of the innate/adaptive distinction. NK cells act as a rapid first line of defense while the adaptive response is being assembled.

Question 4

NK cell killing decisions are determined by the net balance between activating signals (from stress ligands on damaged cells) and inhibitory signals (from MHC-I on healthy cells), rather than by either signal alone.

• T. True
• F. False

Answer: True

This balance model is the key to understanding NK cell discrimination. A normal healthy cell presents both MHC-I (inhibitory) and no stress ligands (no activating signal) — inhibition dominates, the cell is spared. A virally infected cell may downregulate MHC-I and upregulate stress ligands — both changes push toward killing. A cell that retains MHC-I but also gains stress ligands may still be spared if inhibitory signals dominate. The threshold for killing is set by the relative strength of competing receptor signals.

Question 5

Why does the 'missing self' strategy complement cytotoxic T cell immunity rather than duplicate it? Describe the gap each fills.

Model answer: Cytotoxic T cells detect foreign peptides presented on MHC-I — they need MHC-I to be present and loaded with a recognizable antigen. Many viruses and tumor cells exploit this by downregulating MHC-I expression, becoming invisible to T cells. NK cells fill exactly this gap: they are licensed to kill cells that LACK MHC-I. The two systems together make viral immune evasion much harder — a cell can hide from T cells by losing MHC-I, but in doing so it becomes visible to NK cells. Conversely, NK cells spare healthy cells with normal MHC-I expression, preventing autoimmunity.

The key insight is that the two surveillance mechanisms are complementary because they are triggered by opposite signals: T cells need MHC-I present (with foreign peptide); NK cells need MHC-I absent. Together they create a system where downregulating MHC-I is not a successful evasion strategy — it trades one threat for another.