While the intrathymic development of T lymphocytes via positive and negative selection has been well characterized over the past two decades, the processes which regulate the development of pro-thymocytes and immature thymocytes from hematopoietic stem cells (HSC) are poorly understood. Common lymphoid progenitors (CLP), prothymocytes and immature thymocytes express receptors for two cytokines which are known to be involved in lymphoid differentiation: interleukin-7 (IL-7) and c-kit ligand (KL). IL-7 is a stromal derived cytokine which has proliferative, anti-apoptotic and differentiative effects on lymphoid progenitors. The IL-7 receptor (IL-7R) consists of two non-covalently linked subunits, IL-7Ra and the common gamma chain (gamma-c), both of which are members of the type I cytokine receptor superfamily. The IL-7Ra and gamma-c heterodimerize in the presence of IL-7, resulting in activation of multiple pathways, including the JAK-STAT, P13K, and ras-MAPK signal transduction pathways. The lymphopoietic defect in mice rendered IL-7-/-by homologous recombination is less severe than that of mice with an IL-7RcC-/-genotype, suggesting the existence of a complementary pathway that utilizes the IL-7R. KL is the ligand for c-kit, a receptor tyrosine kinase (RTK) expressed by HSC and immature progenitors, including CLP and immature thymocytes. C-kit also activates multiple pathways, including the JAK-STAT pathway. Although the defective HSC and erythroid compartments of mice with mutations of the c-kit or KL loci are well appreciated, the c-kit pathway can also significantly contribute to T lymphopoiesis. Mice with mutations of either KL or c-kit have defective thymopoiesis, which can be corrected by transplantation of a normal thymus or normal HSC, respectively. We have generated IL-7-/- Kit w4 about/w4l and lL-7Ra-/- Kitw41/w41 doubly homozygous mice, both of which have a complete and synergistic loss of thymopoiesis, suggesting an interaction between the IL-7R and c-kit signaling pathways. Preliminary analyses show that c-kit mediates tyrosine phosphorylation and associates with IL-7R. The hypothesis to be tested in the proposed studies is that the IL-7R and c-kit signaling pathways directly interact in T lymphoid differentiation of primitive hematopoietic progenitors. The studies will investigate how interactions between the IL-7R and c-kit signaling pathways occur, including biochemical and imaging studies of receptor association; identification of unique, redundant, or synergistic interactions of STAT molecules activated by the JL-7R (STAT5) and c-kit (STAT1); and changes in gene expression downstream of each pathway. The in vitro studies will be correlated with in vivo interactions of the two cytokine receptor pathways in appropriate mouse strains. Besides their relevance to lymphoid differentiation, the studies will provide a model for how cytokine receptor pathways, one involving a Type I cytokine receptor and the other an RTK, interact during lymphohematopoietic differentiation.
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