positive selection

**Location and cells:** Thymic cortex. Cortical epithelial cells present self-peptide on MHC I and MHC II to double-positive (CD4+CD8+) thymocytes that have rearranged their TCR α chain (the β chain is rearranged earlier, at the double-negative stage, and pairs with pre-Tα).

**Mechanism:** - Thymocytes with TCRs that can recognize self-MHC with weak-to-moderate affinity receive survival signals and continue maturing. - Thymocytes that cannot bind self-MHC receive no signal and die by apoptosis ("death by neglect"). This is the majority (~95%) of thymocytes. - Lineage commitment: MHC II recognition leads to CD4+ (Th) cells and loss of CD8. MHC I recognition leads to CD8+ (Tc) cells and loss of CD4.

**Result:** The surviving T cells are self-MHC restricted. They can recognize antigen only when it is presented on the host's own MHC molecules.

**Positive vs. negative selection:** - Positive selection happens in the cortex. It tests for weak recognition of self-MHC, and failure causes death by neglect. It ensures MHC restriction. - Negative selection happens in the medulla (corticomedullary junction). It tests for strong binding to self-antigen on MHC, and failure to pass causes clonal deletion by apoptosis. It ensures self-tolerance. - Medullary thymic epithelial cells (mTECs) express AIRE, which drives expression of peripheral tissue antigens for negative selection. AIRE mutation causes autoimmune polyendocrine syndrome type 1 (APS-1): chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. - Cortical thymic epithelial cells drive positive selection. Medullary epithelial cells and dendritic cells/macrophages drive negative selection.

**Clinical correlations:** - DiGeorge syndrome (22q11 deletion) causes thymic aplasia or hypoplasia, so there is no positive selection and T-cell deficiency results. Findings: absent thymic shadow, hypocalcemia, cardiac defects, and recurrent viral/fungal infections. - MHC II deficiency (bare lymphocyte syndrome type II) causes absent CD4+ T-cell positive selection, so CD4+ cells are low. - MHC I deficiency (bare lymphocyte syndrome type I, TAP deficiency) causes low CD8+ T cells. - SCID (e.g., RAG or ADA defects) causes failure of TCR rearrangement, so thymocytes never reach positive selection. - Mnemonic: Positive = "Present in cortex, binds MHC weakly (Pass if you can recognize)." Negative = "Not too strong, or you're deleted."

**High-yield:** Positive selection requires TCR recognition of self-MHC (restriction), and negative selection removes strong self-reactivity (tolerance). Failure of negative selection leads to autoimmunity.