The Timing and Abundance of IL-2Rβ (CD122) Expression Control Thymic NKT Cell Generation and NKT1 Subset Differentiation.

Invariant NKT (NKT) 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 NKT cells into the NKT1, NKT2, and NKT17 subsets remains a controversial issue that remains to be resolved. Because cytokine receptor signaling is necessary for NKT cell generation, cytokines are proposed to contribute to NKT 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 NKT cells. While the induction of IL-2Rβ expression on postselection thymocytes is necessary to drive the generation of NKT cells, surprisingly, premature IL-2Rβ expression on immature NKT 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 NKT lineage fate and development, thereby establishing cytokine receptor expression as a critical regulator of thymic NKT cell differentiation.