The Common Cytokine Receptor γ Chain and the Pre-T Cell Receptor Provide Independent but Critically Overlapping Signals in Early α/β T Cell Development

Intracellular signals emanating from cytokine and antigen receptors are integrated during the process of intrathymic development. Still, the relative contributions of cytokine receptor signaling to pre-T cell receptor (TCR) and TCR-mediated differentiation remain undefined. Interleukin (IL)-7 interactions with its cognate receptor complex (IL-7Rα coupled to the common cytokine receptor γ chain, γ(c)) play a dominant role in early thymopoiesis. However, α/β T cell development in IL-7–, IL-7Rα–, and γ(c)-deficient mice is only partially compromised, suggesting that additional pathways can rescue α/β T lineage cells in these mice. We have investigated the potential interdependence of γ(c)- and pre-TCR–dependent pathways during intrathymic α/β T cell differentiation. We demonstrate that γ(c)-dependent cytokines do not appear to be required for normal pre-TCR function, and that the rate-limiting step in α/β T cell development in γ(c) (−) mice does not involve TCR-β chain rearrangements, but rather results from poor maintenance of early thymocytes. Moreover, mice double mutant for both γ(c) and pre-Tα show vastly reduced thymic cellularity and a complete arrest of thymocyte differentiation at the CD44(+)CD25(+) cell stage. These observations demonstrate that the pre-TCR provides the γ(c)-independent signal which allows α/β T cell development in γ(c) (−) mice. Thus, a series of overlapping signals derived from cytokine and T cell receptors guide the process of α/β thymocyte development.