natural killer cell

**Origin and markers:** NK cells derive from the common lymphoid progenitor and are considered innate lymphoid cells (group 1 ILCs). They are large granular lymphocytes. Key surface markers: CD56 (NCAM) and CD16 (FcγRIII); they lack CD3 and a T-cell receptor. They make up about 5–10% of circulating lymphocytes.

**Recognition ("missing self" hypothesis):** - Healthy cells express MHC I, which binds inhibitory receptors on NK cells (KIRs and CD94/NKG2A). This delivers an inhibitory signal, so the cell is spared. - Virus-infected or tumor cells often downregulate MHC I to evade CD8+ T cells. Loss of the inhibitory signal, together with stress-induced ligands (e.g., MICA/MICB binding the activating receptor NKG2D), triggers NK cell activation. - The balance of activating and inhibitory signals determines whether the NK cell kills.

**Effector mechanisms:** 1. Perforin forms pores in the target cell membrane. Granzymes (serine proteases) enter and activate caspases, which causes apoptosis. 2. ADCC (antibody-dependent cell-mediated cytotoxicity): CD16 binds the Fc portion of IgG on antibody-coated targets (e.g., rituximab-coated B cells). 3. Cytokine secretion: IFN-γ activates macrophages. NK cells are an early source of IFN-γ before adaptive immunity develops.

**Activation:** IL-12 (from macrophages and dendritic cells) and type I interferons (IFN-α/β) activate NK cells. IL-2 and IL-15 drive their proliferation and survival (IL-15 is critical for development). The NK–macrophage axis (IL-12 → IFN-γ → macrophage activation) is important for defense against intracellular pathogens.

**Clinical significance:** - Early defense against viruses, especially herpesviruses (HSV, CMV, EBV), and against tumor surveillance. - NK cell deficiency (e.g., GATA2 mutations, MCM4 deficiency) causes severe, recurrent herpesvirus infections. - Chédiak-Higashi syndrome: LYST mutation leads to defective lysosomal trafficking and impaired NK cell degranulation. Features include recurrent pyogenic infections, partial albinism, peripheral neuropathy, and giant granules in leukocytes. - Familial hemophagocytic lymphohistiocytosis (HLH): perforin (PRF1) mutations cause defective NK/CD8 cytotoxicity, leading to uncontrolled immune activation. - Transplant: in hematopoietic stem cell transplant, KIR–HLA mismatch can produce a graft-versus-leukemia effect. - Large granular lymphocyte (LGL) leukemia is a clonal proliferation of T cells or NK cells.

**High-yield comparisons:** - NK cells (innate): no antigen-specific receptor, no memory in the classic sense, and no need for prior sensitization. - CD8+ cytotoxic T cells (adaptive): recognize peptide on MHC I via the TCR and need CD8. The two cell types complement each other. Viruses that downregulate MHC I escape CTLs but become targets for NK cells.