Thymocyte and TEC differentiation are interdependent

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Early stages of thymocyte differentiation occur in the cortex where thymocytes interact with cortical TECs (cTECs) that provide essential signaling molecules for thymocyte differentiation, proliferation, and survival (9, 10). The stereotypical migration of these cells within the thymus suggests that TEC subsets in specific locations throughout the thymus supply different signaling molecules that promote thymocyte maturation. TECs play an essential role in shaping the T cell repertoire by presenting self-peptide/MHC complexes that positively or negatively select thymocytes, resulting in T cells that are self-restricted, i.e. respond to foreign peptides in the context of self-MHC molecules on antigen presenting cells (APCs), and self-tolerant, i.e. fail to mount an immune response to self-peptide/MHC complexes on APCs . Positive selection occurs in the cortex where CD4⁺CD8⁺ thymocytes bearing TCRs with moderate affinity for self-peptide/MHC complexes presented by cTECs are rescued from programmed cell death, terminate either CD8 or CD4 expression and migrate into the medulla (reviewed in (23)). In the medulla, self-peptide/MHC complexes on mTECs and DCs signal thymocytes with high affinity TCRs to undergo apoptosis. This negative selection process purges exported T cells of many self-reactive clones that are capable of causing autoimmunity (24). It is now well established that mTECs play an indispensable role in establishing central tolerance and preventing autoimmunity due to their unique ability to express tissue restricted antigens (TRAs) (25). In addition, mTECs transfer self-epitopes to dendritic cells which are highly efficient in inducing central tolerance (13, 14, 26). Expression of a wide array (but not all) TRAs by mTECs is a regulated by the Aire (autoimmune regulator) gene (27). Expression of Aire and its target TRAs provide an essential deterrent to autoimmunity since patients or mice deficient in Aire develop multiorgan autoimmune disease. In addition, TRAs presented by mTECs promote the development of CD4+CD25+Foxp3+ T regulatory cells and NKT cells both of which actively repress self-reactive peripheral T cells (28-30).

Just as TECs are indispensable for thymocyte development, thymocyte-derived signals are required for the generation of functional cortical and medullary thymic epithelial compartments (reviewed in (31, 32). Mice in which thymocyte development is blocked at or prior to the CD4^-CD8^-CD44⁺CD25⁺ (DN2) stage have severely hypoplastic thymi with a highly disorganized epithelial compartment that is arrested at an immature developmental stage characterized by co-expression of keratin 8 (K8) and K5 and lack of a three-dimensional meshwork (33, 34). In contrast, mice in which thymocyte development is blocked at the later CD4^-CD8^-CD44^-CD25⁺ (DN3) stage have a well-organized cortical epithelial compartment that contains both K8+K5- and K8+K5+ TEC subsets (33, 35, 36) although it is not completely mature (37). Thymocyte-derived signals are also required for mTEC formation. Development of the medullary epithelial compartment is severely impaired when thymocyte development is blocked at or prior to the CD4+ CD8+ double positive (DP) maturation stage (38, 39). This suggests that signals from positively selected thymocytes play a role in development and/or expansion of mTECs in the adult thymus. In the fetal thymus, signals from lymphoid tissue inducer (LTi) cells are required for initial differentiation of Aire expressing mTECs (40). Both mature SP thymocytes and LTi cells express ligands that activate members of the tumor necrosis factor (TNF) receptor superfamily including receptor activator of NFkB (RANK), CD40 and lymphotoxin-b receptor (LTbR) which are expressed on TECs (41-44). The absence of these receptors, their ligands or components of the downstream signaling pathways impairs mTEC development and organization resulting in defective central tolerance and the appearance of autoimmune disease.