CD8 T cell

**Development:** Arise from bone marrow progenitors and mature in the thymus. Double-negative (CD4⁻CD8⁻) → double-positive (CD4⁺CD8⁺) in the cortex. Positive selection (cortex, cortical epithelial cells): T cells must bind self-MHC with adequate affinity; failure leads to death by neglect. Cells that bind MHC I become CD8⁺. Negative selection (corticomedullary junction/medulla; medullary epithelial cells with AIRE-driven self-antigen expression, and dendritic cells/macrophages): strongly self-reactive cells undergo apoptosis. Defective AIRE causes autoimmune polyendocrine syndrome type 1 (APS-1).

**Activation (needs 2 signals):** - Signal 1: TCR (with CD3) binds peptide–MHC I on the APC; CD8 coreceptor binds the MHC I α3 domain. - Signal 2: costimulation, with CD28 on the T cell binding B7 (CD80/86) on the APC. - Naive CD8 cells need cross-presentation by dendritic cells (exogenous antigen loaded onto MHC I) and help from CD4 Th1 cells (IL-2, IFN-γ) for full activation. - IL-2 drives clonal expansion. Without signal 2, cells become anergic.

**Antigen processing (MHC I pathway):** Endogenous (cytosolic) proteins are degraded by the proteasome. Peptides enter the ER via TAP. ER chaperones (calnexin, calreticulin, tapasin) help load them onto MHC I, which is then transported to the surface (β2-microglobulin is required). Defects: TAP deficiency (bare lymphocyte syndrome type I), and viral or tumor downregulation of MHC I, which makes cells targets for NK cells ("missing self").

**Effector mechanisms:** - Perforin forms pores in the target cell membrane. Granzymes (serine proteases) enter and activate caspases, causing apoptosis. - Fas ligand (on CTL) binds Fas (CD95) on the target, activating caspases. - Secretion of IFN-γ and TNF-α. - Granulysin is also released.

**Clinical significance:** - Defense against intracellular pathogens (viruses, some intracellular bacteria), and tumor surveillance. - Acute cellular rejection of transplants (CD8 and CD4 responses to donor MHC) and graft-versus-host disease. - Type IV (delayed-type) hypersensitivity: CD8 T cells mediate direct cell cytotoxicity (e.g., contact dermatitis, in part; SJS/TEN, drug reactions with HLA associations like carbamazepine–HLA-B*15:02 and abacavir–HLA-B*57:01). - HIV: CD4 loss leads to impaired CD8 function; CD8 T cell exhaustion and PD-1 expression follow chronic infection. In HIV, the CD4:CD8 ratio inverts (<1). - Immunotherapy: checkpoint inhibitors (anti-PD-1 such as pembrolizumab and nivolumab; anti-CTLA-4 such as ipilimumab) reinvigorate CD8 responses against tumors. CAR-T therapy is also used. - Autoimmunity: CD8 T cells contribute to type 1 diabetes (β-cell destruction), multiple sclerosis, and others. - Memory CD8 cells provide rapid recall responses. - Mononucleosis (EBV): atypical lymphocytes (Downey cells) on smear are reactive CD8⁺ T cells.

**Markers/mnemonic:** CD3⁺, CD8⁺, TCR αβ. "Rule of 8": MHC I (1 × 8 = 8) and MHC II (2 × 4 = 8). CD8 binds MHC I; CD4 binds MHC II.

**Contrast with CD4:** Helper T cells (MHC II, exogenous antigens, cytokine secretion) vs. CD8 cells (MHC I, endogenous antigens, direct killing).