Abstract
In the thymus, medullary thymic epithelial cells (mTEC) determine the fate of newly selected CD4+ and CD8+ single positive (SP) thymocytes. For example, mTEC expression of Aire controls intrathymic self‐antigen availability for negative selection. Interestingly, alterations in both Foxp3+ Regulatory T‐cells (T‐Reg) and conventional SP thymocytes in Aire−/− mice suggest additional, yet poorly understood, roles for Aire during intrathymic T‐cell development. To examine this, we analysed thymocytes from Aire −/− mice using Rag2GFP and Foxp3 expression, and a recently described CD69/MHCI subset definition of post‐selection CD4+ conventional thymocytes. We show that while Aire is dispensable for de novo generation of conventional αβT‐cells, it plays a key role in controlling the intrathymic T‐Reg pool. Surprisingly, a decline in intrathymic T‐Reg in Aire−/− mice maps to a reduction in mature recirculating Rag2GFP− T‐Reg that express CCR6 and re‐enter the thymus from the periphery. Furthermore, we show mTEC expression of the CCR6 ligand CCL20 is reduced in Aire−/− mice, and that CCR6 is required for T‐Reg recirculation back to the thymus. Collectively, our study re‐defines requirements for late stage intrathymic αβT‐cell development, and demonstrates that Aire controls a CCR6‐CCL20 axis that determines the developmental makeup of the intrathymic T‐Reg pool.
Highlights
In the thymus, distinct stromal cell types support the generation of functionally competent αβT-cells
We have studied mechanisms controlling the developmental progression of CD4+ thymocytes, and examined the impact of the thymus medulla on this process
The thymus medulla contains Foxp3+ T-Reg that branch off from the programme of conventional thymocyte development during the CD4+ stage [19, 35, 36], and medullary thymic epithelial cells (mTEC) play an essential role in the generation of Foxp3+ T-Reg and their precursors [19, 20]
Summary
Distinct stromal cell types support the generation of functionally competent αβT-cells. The same study described ‘Semi-Mature’ (SM, CD69+MHCIlo), ‘Mature 1’ (M1, CD69+MHCI+) and ‘Mature 2’ (M2, CD69−MHCI+) subsets that represent an accurate developmental sequence of CD4+ SP thymocytes, with functional maturation residing within M1 and M2 cells [28, 32] While these studies define SP thymocyte heterogeneity, the role of the thymus medulla in controlling transit through these stages is not clear. The role of mTEC and Aire in late stage CD4+ αβT-cell development is poorly understood Given these uncertainties, we have studied mechanisms controlling the developmental progression of CD4+ thymocytes, and examined the impact of the thymus medulla on this process. Our study redefines the requirements of post-selection intrathymic T-cell development, and describes a new role for Aire in controlling migration of T-Reg between peripheral tissues and the thymus
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