Macrophages engulfing apoptotic thymocytes produce retinoids to promote selection, differentiation, removal and replacement of double positive thymocytes

Abstract

The thymus provides the microenvironment in which thymocytes develop into mature T-cells, and interactions with thymic stromal cells are thought to provide the necessary signals for thymocyte maturation. Recognition of self-MHC by T-cells is a basic requirement for mature T-cell functions, and those thymocytes that do not recognize or respond too strongly to the peptide-loaded self-MHC molecules found in the thymus undergo apoptosis. As a result, 95% of the thymocytes produced will die and be subsequently cleared by macrophages. This review describes a complex crosstalk between developing thymocytes and engulfing macrophages which is mediated by retinoids produced by engulfing macrophages. The interaction results in the harmonization of the rate of cell death of dying double positive cells with their clearance and replacement, and in promotion of the differentiation of the selected cells in the thymus.

Keywords: 9-cis RA; 9-cis retinoic acid; ADH; ARAT; ATRA; All-trans-DRA; Apoptosis; BAI1; CRABP; CRBP; Engulfment; Gas6; LRAT; LXR; MFG-E8; MHC; Macrophages; PPAR; PS; RA; RALDH; RAR; RARE; RBP; RXR; RXR response element; RXRE; RetSat; Retinaldehyde dehydrogenase; Retinoic acid; SDR; SR; T cell receptor; T-cell immunoglobulin- and mucin-domain-containing molecule; TCR; TEC; TG2; Thymus; Tim4; acyl-CoA:retinol acyltransferase; alcohol dehydrogenase; all-trans retinoic acid; all-trans-dihydroretinoic acid; brain-specific angiogenesis inhibitor 1; cellular retinoic acid-binding protein; cellular retinol-binding protein; growth arrest-specific-6; lecithin:retinol acyltransferase; liver X receptor; major histocompatibility complex; milk fat globule EGF-factor 8; peroxisome proliferator-activated receptor; phosphatidylserine; retinaldehyde dehydrogenase; retinoic acid; retinoic acid receptor; retinoic acid response element; retinoid X receptor; retinol saturase; retinol-binding protein; scavenger receptor; short-chain dehydrogenase/reductase; thymic epithelial cell; transglutaminase 2.