PRO-THYMOCYTE EXPANSION BY C-KIT AND THE COMMON CYTOKINE RECEPTOR-GAMMA CHAIN IS ESSENTIAL FOR REPERTOIRE FORMATION

Growth factors have been implicated in thymocyte development, but muta nts lacking cytokines, or their receptors, have failed to reveal essen tial roles for growth/differentiation factors in the thymus. Mutations in the receptor tyrosine kinase c-kit and the common cytokine recepto r gamma chain (gamma(c)) reduce cellularity, but are permissive for th ymocyte development. We now report that thymocyte development is compl etely abrogated in mice lacking both c-kit and gamma(c) (c-kit(-)gamma (c)(-)). Thymic hypocellularity is so severe that the T cell receptor repertoire fails to form except for monoclonal or oligoclonal beta cha in DJ rearrangements. B lymphopoiesis is only mildly reduced in c-kit( -)gamma(c)(-) as compared with c-kit(+)gamma(c)(-) mice, and hematolog ical values are identical comparing c-kit-deficient and c-kit(-)gamma( c)(-) mice. These experiments reveal essential, overlapping, and syner gistic functions for two distinct signaling pathways, one utilizing c- kit and the other cytokine receptor gamma(c) complexes coupling to Jan us kinases and signal transducers and activators of transcription.