Abstract
Invariant NKT (iNKT) cells are thymus-generated innate-like T cells, comprised of three distinct subsets with divergent effector functions. The molecular mechanism that drives the lineage trifurcation of immature iNKT cells into the NKT1, NKT2, and NKT17 subsets remains a controversial issue that remains to be resolved. Because cytokine receptor signaling is necessary for iNKT cell generation, cytokines are proposed to contribute to iNKT subset differentiation also. However, the precise roles and requirements of cytokines in these processes are not fully understood. Here, we show that IL-2Rβ, a nonredundant component of the IL-15 receptor complex, plays a critical role in both the development and differentiation of thymic iNKT cells. While the induction of IL-2Rβ expression on postselection thymocytes is necessary to drive the generation of iNKT cells, surprisingly, premature IL-2Rβ expression on immature iNKT cells was detrimental to their development. Moreover, while IL-2Rβ is necessary for NKT1 generation, paradoxically, we found that the increased abundance of IL-2Rβ suppressed NKT1 generation without affecting NKT2 and NKT17 cell differentiation. Thus, the timing and abundance of IL-2Rβ expression control iNKT lineage fate and development, thereby establishing cytokine receptor expression as a critical regulator of thymic iNKT cell differentiation.
Highlights
Cytokines of the common g-chain family play critical roles in the generation and differentiation of T cells in the thymus [1,2,3]
We found that invariant NKT (iNKT) cells, as identified by PBS-57-loaded CD1d tetramers (CD1dTet+), arise as early as in stage I, and that they were prominent in stage II (Figure 1A, bottom)
The gc family cytokine IL-15 is a critical factor in thymic iNKT cell generation that contributes to the subset specification of iNKT cells [11]
Summary
Cytokines of the common g-chain (gc) family play critical roles in the generation and differentiation of T cells in the thymus [1,2,3]. Cytokines can specify the differentiation of iNKT cells in the thymus It remains unclear why some iNKT precursors would respond to IL-15 and become NKT1 cells, whereas other precursors are refractory to IL-15 and choose other lineage fates. This problem is further compounded by all iNKT cells expressing the same semi-invariant TCR so that differences in the TCR repertoire are unlikely to play a significant role in subset differentiation. Instead, we consider it likely that differences in the timing or abundance of cytokine receptors could determine the responsiveness to subsetspecifying cytokines
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