Abstract
SummaryCurrent models of Foxp3+ regulatory T cell (Treg) development involve CCR7-mediated migration of thymocytes into the thymus medulla to enable essential interactions with medullary epithelium. However, increased Foxp3+ thymic Treg numbers in Ccr7−/− mice challenge this view, and the role of CCR7 in Treg development, emigration, and/or recirculation is unknown. Here, we have examined CCR7 and Rag2pGFP levels during Treg development and generated Rag2pGFPCcr7−/− mice to study its impact on the intrathymic Treg pool. We reveal surprising developmental heterogeneity in thymocytes described as Treg precursors, showing that they contain recirculating CCR6+CCR7−Rag2pGFP− T cells. Although CCR7 defines bona fide Rag2GFP+ Treg precursors, it is not required for Treg production and emigration. Rather, we show that lack of CCR7 renders the thymus more receptive to Treg thymus homing. Our study reveals a role for CCR7 in limiting Treg recirculation back to the thymus and enables separation of the mechanisms controlling Treg production and thymic recirculation.
Highlights
In the thymus, positive selection generates subsets of CD4+ abT cells that are functionally distinct, and immature CD4+CD8+ thymocytes represent the precursors of both CD4+ conventional helper and Foxp3+ regulatory T cells (Tregs)
While positive selection of conventional CD4+ thymocytes requires cortical thymic epithelial cells (Murata et al, 2007), their further differentiation can take place independently of the thymic medulla, which instead operates as a site for negative selection (Boehm et al, 2003; Cowan et al, 2013; Koble and Kyewski, 2009)
Entry into the medulla is known to be triggered by positive selection, with induction of CCR7 expression altering the migratory ability of newly selected thymocytes and enabling access medullary thymic microenvironments (Kwan and Killeen, 2004; Liston et al, 2008; Ueno et al, 2004)
Summary
Current models of Foxp3+ Treg development indicate that CCR7 controls thymus medulla entry for Treg precursor generation. By redefining newly produced Treg precursors, Cowan et al show that, while CCR7 is dispensable for Treg development, it influences the intrathymic Treg pool by rate-limiting peripheral Treg recirculation back to the thymus.
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