thymic selection

**Overview** Progenitors from bone marrow enter the thymus as double-negative (CD4-/CD8-) thymocytes, rearrange the TCR genes (RAG1/RAG2), become double-positive (CD4+CD8+), and then undergo selection. Result: single-positive naive CD4+ or CD8+ T cells that are self-MHC restricted and self-tolerant.

**1. Positive selection (thymic CORTEX)** - Cortical epithelial cells present self-peptide on MHC I and MHC II to double-positive thymocytes. - The TCR must bind self-MHC with at least weak affinity. Cells that fail to bind die by neglect (apoptosis). - Outcome: MHC restriction. MHC II binding gives CD4+ cells; MHC I binding gives CD8+ cells. - Clinical correlates: MHC II deficiency (bare lymphocyte syndrome) causes few CD4+ T cells. MHC I deficiency causes few CD8+ T cells.

**2. Negative selection (thymic MEDULLA, and corticomedullary junction)** - Medullary thymic epithelial cells (mTECs), dendritic cells, and macrophages present self-antigens. High-affinity binding triggers apoptosis (clonal deletion, mediated partly by Bim) or diversion to regulatory T cells (FoxP3+ Tregs). - AIRE (autoimmune regulator) is a transcription factor in mTECs. It drives expression of peripheral tissue-specific antigens (e.g., insulin, thyroglobulin) so that thymocytes reactive to these antigens can be deleted. - Outcome: central tolerance. - Clinical correlates: - AIRE mutation causes APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APS-1). It presents with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency (Addison disease). - Defective negative selection contributes to autoimmunity.

**Key points** - Positive selection asks "Can you recognize self-MHC?" Negative selection asks "Do you react too strongly to self?" - Cortex = positive; medulla = negative. Mnemonic: "Positive = Cortex (both have 'C-P' feel); Negative = Medulla." - Only about 2-5% of thymocytes survive. - Central tolerance (thymus for T cells, bone marrow for B cells) is distinct from peripheral tolerance (anergy, Tregs, deletion, immune privilege). - Related conditions: DiGeorge syndrome (22q11.2 deletion) causes thymic aplasia and absent T cells. SCID involves defective T cell development (e.g., RAG mutations, ADA deficiency, IL-2Rγ chain defects). Thymoma is associated with myasthenia gravis and, rarely, pure red cell aplasia and hypogammaglobulinemia (Good syndrome). - Mature naive T cells leave the thymus expressing CD3 and either CD4 or CD8, then circulate to secondary lymphoid organs.