cytotoxic T cell

**Development and markers:** Arise from hematopoietic stem cells, mature in the thymus. Express TCR + CD3 + CD8. Positive selection in the thymic cortex (TCR must bind self-MHC I weakly; failure leads to death by neglect). Negative selection in the thymic medulla (strong self-antigen binding leads to apoptosis; AIRE promotes expression of peripheral self-antigens). MHC I is present on all nucleated cells (and not on RBCs), and CD8 binds the α3 domain of MHC I (β2-microglobulin is the light chain). Rule of 8: MHC class I x CD8 = 8 (MHC II x CD4 = 8).

**Activation (requires 2 signals):** 1. Signal 1: TCR binds peptide-MHC I on an antigen-presenting cell. Endogenous (cytosolic) antigens are degraded by the proteasome, transported into the ER by TAP, loaded onto MHC I, then displayed on the surface. Cross-presentation by dendritic cells allows exogenous antigen to be loaded on MHC I. 2. Signal 2: Costimulation, with B7 (CD80/86) on the APC binding CD28 on the T cell. Helper T cell cytokines (IL-2 from CD4+ Th1 cells) support full activation and clonal expansion. Without signal 2, the cell becomes anergic.

**Effector mechanisms (killing):** - Perforin forms pores in the target cell membrane. - Granzymes (serine proteases) enter through the pores and activate caspases, causing apoptosis. - Fas ligand (FasL) on the CTL binds Fas (CD95) on the target, activating the caspase cascade. - Secretes IFN-γ and TNF-α, which upregulate MHC I expression and activate macrophages.

**Clinical significance:** - Viral infections: key to clearing intracellular infections (e.g., EBV, in which atypical lymphocytes in infectious mononucleosis are reactive CD8+ T cells). - Tumor surveillance: kills cancer cells expressing abnormal antigens. Tumors can evade by downregulating MHC I. Natural killer (NK) cells compensate, since they kill cells lacking MHC I ("missing self"). - Transplant rejection: CTLs mediate acute cellular rejection (type IV hypersensitivity) and graft-versus-host disease. - Type IV (delayed-type) hypersensitivity: CD8+ T cells mediate contact dermatitis (e.g., poison ivy, nickel) alongside CD4+ cells, and drug reactions such as SJS/TEN. - HIV: primarily infects CD4+ cells (gp120 binds CD4 and CCR5/CXCR4), but CD8+ T cells initially control viremia. In AIDS the CD4:CD8 ratio falls to less than 1.5. - Immune checkpoint inhibitors: Tumors express PD-L1, which binds PD-1 on CTLs and causes exhaustion. Anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab), and anti-CTLA-4 (ipilimumab) restore CTL activity and can cause immune-related adverse events. - Immunodeficiency: MHC I deficiency (bare lymphocyte syndrome type I, TAP mutation) leads to reduced CD8+ T cells and recurrent respiratory infections. Viral evasion: some viruses (e.g., HSV, CMV) downregulate MHC I, and NK cells counter this. - Memory CD8+ T cells persist after infection and provide faster secondary responses.

**High-yield contrast:** CD4+ helper T cells recognize MHC II and orchestrate the response through cytokines; CD8+ cytotoxic T cells recognize MHC I and directly kill. NK cells are innate, need no prior sensitization, and kill via perforin/granzymes when MHC I is absent or reduced.