Distinct Roles for Signals Relayed through the Common Cytokine Receptor γ Chain and Interleukin 7 Receptor α Chain in Natural T Cell Development

The commitment, differentiation, and expansion of mainstream α/β T cells during ontogeny depend on the highly controlled interplay of signals relayed by cytokines through their receptors on progenitor cells. The role of cytokines in the development of natural killer (NK)1(+) natural T cells is less clearly understood. In an approach to define the role of cytokines in the commitment, differentiation, and expansion of NK1(+) T cells, their development was studied in common cytokine receptor γ chain (γc) and interleukin (IL)-7 receptor α (IL-7Rα)–deficient mice. These mutations block mainstream α/β T cell ontogeny at an early prethymocyte stage. Natural T cells do not develop in γc-deficient mice; they are absent in the thymus and peripheral lymphoid organs such as the liver and the spleen. In contrast, NK1(+) T cells develop in IL-7Rα–deficient mice in the thymus, and they are present in the liver and in the spleen. However, the absolute number of NK1(+) T cells in the thymus of IL-7Rα–deficient mice is reduced to ∼10%, compared to natural T cell number in the wild-type thymus. Additional data revealed that NK1(+) T cell ontogeny is not impaired in IL-2– or IL-4–deficient mice, suggesting that neither IL-2, IL-4, nor IL-7 are required for their development. From these data, we conclude that commitment and/or differentiation to the NK1(+) natural T cell lineage requires signal transduction through the γc, and once committed, their expansion requires signals relayed through the IL-7Rα.