NK cell

**Lineage and markers:** NK cells arise from the common lymphoid progenitor. They are classified as innate lymphoid cells (group 1 ILCs). They are large granular lymphocytes. Markers: CD56 (NCAM) and CD16 (FcγRIII). They are CD3-negative, so they are not T cells. They lack a TCR and do not undergo V(D)J recombination, so they have no antigen-specific receptor and no memory in the classic sense.

**Activation (balance of signals):** - Activating receptors: NKG2D binds stress-induced ligands (MICA/MICB) on stressed, infected, or transformed cells. CD16 binds the Fc portion of IgG on antibody-coated cells. - Inhibitory receptors: KIRs and CD94/NKG2A bind MHC class I (HLA-A, B, C, and HLA-E). Normal cells express MHC I, which keeps NK cells inhibited. - "Missing self" hypothesis: viruses (e.g., CMV, HSV) and tumors often downregulate MHC I to evade CD8+ T cells. NK cells detect this loss and kill the cell. Cells that lose MHC I and also express stress ligands are killed.

**Effector mechanisms:** 1. Perforin forms pores in the target cell membrane. Granzymes enter and activate caspases, which induces apoptosis. 2. ADCC (antibody-dependent cellular cytotoxicity): CD16 binds IgG (mainly IgG1 and IgG3) on target cells. Examples include rituximab (anti-CD20) and trastuzumab (anti-HER2). 3. Cytokines: IFN-γ activates macrophages. IL-12 (from macrophages and dendritic cells) and IL-15 activate NK cells. IL-2 also enhances their activity. Type I interferons (IFN-α/β) also activate NK cells.

**NK cells vs. cytotoxic T cells:** - NK cells are innate, need no prior sensitization, act early (the first days of a viral infection), and recognize missing MHC I. - CD8+ T cells are adaptive, antigen-specific, MHC I-restricted, and need clonal expansion. - Both use perforin and granzymes.

**Clinical associations:** - Chédiak-Higashi syndrome: LYST mutation causes defective lysosomal trafficking. This leads to impaired NK cell and phagocyte function (giant granules in leukocytes). Findings: recurrent pyogenic infections, partial albinism, peripheral neuropathy, and progressive neurodegeneration. - NK cell deficiency (e.g., GATA2 mutations, MCM4, and others) causes severe herpesvirus infections (HSV, CMV, VZV). - Familial hemophagocytic lymphohistiocytosis (HLH): perforin (PRF1) and other cytotoxic granule defects cause impaired NK and CTL killing, uncontrolled macrophage activation, fever, cytopenias, and high ferritin. - Hemolytic disease/transplant: NK cells contribute to graft-versus-leukemia effects and to rejection of bone marrow grafts (hybrid resistance). - NK/T-cell lymphoma (extranodal, nasal type) is associated with EBV. - Large granular lymphocytic (LGL) leukemia can involve NK cells. - Cancer immunotherapy: monoclonal antibodies work partly through NK-mediated ADCC, and CAR-NK cells are being investigated.

**High-yield pearls:** Markers CD16+/CD56+/CD3−. Part of the innate immune system and kills by perforin/granzyme. Detects "missing self." Activated by IL-12, IL-15, and IFN-α/β. Secretes IFN-γ. Mediates ADCC via CD16. Defective in Chédiak-Higashi syndrome.