DISTINCT ROLES FOR SIGNALS RELAYED THROUGH THE COMMON CYTOKINE RECEPTOR-GAMMA CHAIN AND INTERLEUKIN-7 RECEPTOR-ALPHA CHAIN IN NATURAL T-CELL DEVELOPMENT

The commitment, differentiation, and expansion of mainstream alpha/bet a T cells during ontogeny depend on the highly controlled interplay of signals relayed by cytokines through their receptors on progenitor ce lls. The role of cytokines in the development of natural killer (NK)1( +) natural T cells is less clearly understood. In an approach to defin e the role of cytokines in the commitment, differentiation, and expans ion of NK1(+) T cells, their development was studied in common cytokin e receptor gamma chain (gamma c) and interleukin (IL)-7 receptor alpha (IL-7R alpha)-deficient mice. These mutations block mainstream alpha/ beta T cell ontogeny at an early prethymocyte stage. Natural T cells d o not develop in gamma c-deficient mice; they are absent in the thymus and peripheral lymphoid organs such as the liver and the spleen. In c ontrast, NK1(+) T cells develop in IL-7R alpha-deficient mice in the t hymus, and they are present in the liver and in the spleen. However, t he absolute number of NK1(+) T cells in the thymus of IL-7R alpha-defi cient mice is reduced to similar to 10%, compared to natural T cell nu mber in the wild-type thymus. Additional data revealed that NK1(+) T c ell ontogeny is not impaired in IL-2- or IL-4-deficient mice, suggesti ng that neither IL-2, IL-4, nor IL-7 are required for their developmen t. From these data, we conclude that commitment and/or differentiation to the NK1(+) natural T cell lineage requires signal transduction thr ough the gamma c, and once committed, their expansion requires signals relayed through the IL-7R alpha.