Abstract
While CD69 may regulate thymocyte egress by inhibiting S1P1 expression, CD69 expression is not thought to be required for normal thymocyte development. Here we show that CD69 is in fact specifically required for the differentiation of mature NKT2 cells, which do not themselves express CD69. Mechanistically, CD69 expression is required on CD24+ PLZFhi innate precursors for their retention in the thymus and completion of their differentiation into mature NKT2 cells. By contrast, CD69-deficient CD24+ PLZFhi innate precursors express S1P1 and prematurely exit the thymus, while S1P1 inhibitor treatment of CD69-deficient mice retains CD24+ PLZFhi innate precursors in the thymus and restores NKT2 cell differentiation. Thus, CD69 prevents S1P1 expression on CD24+ PLZFhi innate precursor cells from aborting NKT2 differentiation in the thymus. This study reveals the importance of CD69 to prolong the thymic residency time of developing immature precursors for proper differentiation of a T cell subset.
Highlights
While CD69 may regulate thymocyte egress by inhibiting S1P1 expression, CD69 expression is not thought to be required for normal thymocyte development
To gain insight into why NKT2 cell differentiation depends on CD69 expression, we considered the fact that CD69, by interacting with and suppressing S1P1 surface expression, inhibits thymocyte egress from the thymus[12,13,14]
The present study significantly enhances our understanding of very-early invariant natural killer T (iNKT) cell development by defining two subsets of stage 0 iNKT cells: CD24+CD44low and CD24+CD44hi innate precursor cells
Summary
While CD69 may regulate thymocyte egress by inhibiting S1P1 expression, CD69 expression is not thought to be required for normal thymocyte development. TCRs that recognize glycolipid antigens presented by cortical thymocytes signal differentiation into three distinct subsets of iNKT effector cells: NKT1, NKT2, and NKT17 cells[2,3,4,5,6], which can be signaled to rapidly produce interferon-γ (IFNγ), interleukin-4 (IL-4), and IL-17 effector cytokines, respectively, during their development in the thymus. These three iNKT subsets are thought to arise as completely distinct effector subsets from iNKT precursors in the thymus[7], but it is not known how iNKT precursors in the thymus are signaled to adopt different iNKT effector lineage fates. This study documents the importance of the CD69-mediated prolongation of the thymic residency time for the differentiation of a T cell subset and enhances the understanding of when and how distinct effector fates are determined during iNKT cell development in the thymus
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