Differential Requirement for CCR4 and CCR7 during the Development of Innate and Adaptive αβT Cells in the Adult Thymus

Abstract

αβT cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters αβT cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple αβT cell lineages, notably the induction of Foxp3+ regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional αβT cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple αβT cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire−/− mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3+ regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple αβT cell lineages to access the thymic medulla.

CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells

“…Interestingly, this may reflect a minor role for CCR4 in an earlier developmental stage. Aire-dependent expression of CCR4 has been shown to occur during the development of multiple αβ T cell lineages in the thymus, although CCR4 was not unanimously found to be required for T cell development in these studies (32,33). Thus, CCR4 may play a role in the T cell lineage at the common lymphocyte progenitor stage, during thymic emigration, or even at the level of systemic circulation.…”

Histone Deacetylase 3 Is Required for T Cell Maturation

“…We found that T cell maturation was independent of migration or egress as SP thymocytes from CD4-cre HDAC3 cKO mice regulate expression of CCR4, CCR7, CCR9 and S1P1 as expected (Figure 4). Conversely, CCR7/CCR4 double KO mice which do not migrate into the medulla display normal maturation of conventional CD4 SP thymocytes, although the development of nTreg and iNKT cells is severely curtailed (5). Mice deficient in S1PR1 or treated with FTY720 show an accumulation of CD24 lo Qa2 hi mature SP thymocytes (8).…”

Development of invariant natural killer T cells

“…Interestingly, iNKT cell development depends on normal thymus medulla development and interaction with mTECs. Expression of the chemokine receptor CCR7 enables developing iNKT cells to enter the thymic medulla [67] and gain access to mTECs, which play an important role by providing IL-15 transpresentation [47] necessary to the complete development of iNKT1 cells. Because iNKT2 and iNKT17 cells were also found within the medulla [7 •• ], it is likely that other chemokine receptors regulate localization as well.…”