Formation of the Intrathymic Dendritic Cell Pool Requires CCL21-Mediated Recruitment of CCR7+ Progenitors to the Thymus.

Abstract

During αβ T cell development in the thymus, migration of newly selected CD4+ and CD8+ thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αβ TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα+ conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2. In contrast, although Sirpα− conventional DC type 1 (cDC1) are known to arise intrathymically from immature progenitors, the precise nature of such thymus-colonizing progenitors and the mechanisms controlling their thymus entry are unclear. In this article, we report a selective reduction in thymic cDC1 in mice lacking the chemokine receptor CCR7. In addition, we show that the thymus contains a CD11c+MHC class II−Sirpα−Flt3+ cDC progenitor population that expresses CCR7, and that migration of these cells to the thymus is impaired in Ccr7−/− mice. Moreover, thymic cDC1 defects in Ccr7−/− mice are mirrored in plt/plt mice, with further analysis of mice individually lacking the CCR7 ligands CCL21Ser (Ccl21a−/−) or CCL19 (Ccl19−/−) demonstrating an essential role for CCR7-CCL21Ser during intrathymic cDC1 development. Collectively, our data support a mechanism in which CCR7-CCL21Ser interactions guide the migration of cDC progenitors to the thymus for correct formation of the intrathymic cDC1 pool.