Conditional deletion reveals a role for Sos1 in pre‐TCR signaling and thymocyte development

Signal transduction through two receptors, the T cell antigen receptor (TCR) and the pre‐TCR, regulates specific stages of thymocyte development. TCR stimulation rapidly triggers tyrosine phosphorylation of the adaptor protein LAT, which signals to Ras via two RasGEFs, RasGRP and Sos1/2. Both LAT and Ras are required for pre‐TCR and TCR‐mediated developmental signals, whereas the relative importance of RasGRP and Sos is not fully understood, as Sos1−/− mice die in utero, whereas Sos2−/− mice are phenotypically normal. To avoid embryonic lethality, we generated sos1‐floxed mice, and crossed these with mice expressing Lck‐Cre to generate T cell‐specific Sos1 knockout mice. Deletion of Sos1 caused a 50% reduction in thymic cellularity, and a partial block in pre‐TCR mediated proliferation and development. Furthermore, Sos1, but not RasGRP1, was required for maximal anti‐CD3ε stimulated proliferation in Rag2−/− mice. Purified DP thymocytes from Sos1 knockout mice show reduced TCR‐induced LAT phosphorylation, ERK activation, and calcium flux. These data demonstrate that Sos1 is an important regulator of pre‐TCR‐mediated development and can modulate signal transduction in developing thymocytes.