The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development

Abstract

A key role of the thymic medulla is to negatively select autoreactive CD4+ and CD8+ thymocytes, a process important for T cell tolerance induction. However, the involvement of the thymic medulla in other aspects of αβ T cell development, including the generation of Foxp3+ natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69+Qa2− CD4 single-positive thymocytes mature to the late CD69−Qa2+ stage in the absence of RelB-dependent medullary thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extrathymically is observed within the CD69+CCR7−/loCCR9+ subset of conventional SP4 thymocytes, providing evidence for an independence from medullary support by the earliest stages after positive selection. In contrast, Foxp3+ nTreg cell development is medullary dependent, with mTECs fostering the generation of Foxp3−CD25+ nTreg cell precursors at the CD69+CCR7+CCR9− stage. Our results demonstrate a differential requirement for the thymic medulla in relation to CD4 conventional and Foxp3+ thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3+ nTreg cell development through the generation of Foxp3−CD25+ nTreg cell precursors.

Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice

“…Albeit negative selection seemed normal at a polyclonal level, we cannot exclude the possibility that rare autoreactive thymocytes escape from the p53cKO thymus. In line with previous studies, 32 we reason that the underrepresentation of regulatory T cells and mature SP4 represents the footprint of a decrease in the availability of mTEC niches. Concordantly, mild signs of autoimmune manifestations unfolded in aged p53cKO mice and in immunodeficient mice receiving p53cKO-derived thymocytes.…”

Distinct phases in the positive selection of CD8+T cells distinguished by intrathymic migration and T-cell receptor signaling patterns

“…The switch in expression of CCR7 and CXCR4 can be detected on a substantial proportion of MHC class I-selected, but not MHC class II-selected DP thymocytes (15)(16)(17). Therefore, the timing of the switch in chemokine responsiveness and migration to the medulla appears to differ during CD4 versus CD8 T-cell development.…”

“…Mature SP thymocytes remain in the thymus for 4-5 d (33) and thus may accumulate to outnumber the MHC class I-selected DP thymocytes in the steady-state thymus. Moreover, analysis of steady-state MHC class II-restricted thymocytes suggests that the switch in chemokine-receptor expression occurs during the early CD4 SP stage rather than at the DP stage (15)(16)(17). Therefore, it seems likely that steady-state medullary thymocytes consist primarily of CD4 and CD8 SP thymocytes, along with DP thymocytes bearing class I MHC-restricted TCR.…”

“…Conversely, mature SP thymocytes express CCR7 and have diminished expression of CXCR4 (12)(13)(14). For MHC class IIrestricted selection, chemokine-receptor changes appear to occur early during the SP stage whereas thymocytes undergoing positive selection via MHC class I up-regulate CCR7 at the DP stage (15)(16)(17). However, it is unclear whether the switch in chemokinereceptor expression and migration to the medulla occurs after positive selection is complete, or whether positive selection continues after thymocytes migrate to the medulla.…”

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

“…Although the thymic cortex is necessary for thymocyte expansion and positive selection, the primary role of the thymic medulla is in the generation of selftolerance via negative selection and the generation of regulatory T cells (3)(4)(5). Failure to establish or maintain self-tolerance causes autoimmunity, which has a major impact on human health.…”