Abstract
The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTβR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTβR controls CD104+CCL21+ mTEClow that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues.
Highlights
The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood
We examined mTEClow in the 8–12-week adult mouse thymus
We found that thymic tuft cells[15,16], defined here by the expression of the tuft cell-specific enzyme DCLK118, were detectable within the CD104−CCL21− mTEClow subset (Fig. 1a)
Summary
The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development This mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. In addition to generating and shaping the conventional αβT cell pool, thymic microenvironments foster other T cell lineages that are classed as ‘unconventional’ as they express antigen receptors that do not recognise MHC These include CD1d-restricted invariant natural killer T cells (iNKT cells) that via their steady-state production of cytokines, including interleukin-4 (IL-4)[7,8,9], play important roles in the control of immune responses[10,11]. Our findings identify the regulation of mTEC heterogeneity by LTβR as an intrathymic mechanism that determines the availability and function of iNKT cells in both the thymus and periphery
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