RasGRP essential for mouse thymocyte differentiation and TCR signaling

The Ras signaling pathway plays a critical role in thymopoiesis and T cell activation, but the mechanism of Ras regulation is controversial. At least one mode of Ras regulation in T cells involves the messenger diacylglycerol (DAG). RasGRP, a Ras activator with a DAG-binding Cl domain, is expressed inT cells and thymocytes. Here we show that thymi of RasGRP-null mutant mic e have approximately normal numbers of immature thymocytes but a marked def iciency of mature, single-positive (CD4(+)CD8(-) and CD4(-)CD8(+)) thymocyt es. In Ras signaling and proliferation assays, mutant thymocytes showed a c omplete lack of response to DAG analogs or T cell receptor (TCR) stimulatio n by antibodies. Thus, TCR and DAG are linked through RasGRP to Ras signali ng.