Deconstructing Ras Signaling in the Thymus

Thymocytes must transit at least two distinct developmental checkpoints, governed by signals that emanate from either the pre-T cell receptor (pre-TCR) or the TCR to the small G protein Ras before emerging as functional T lymphocytes. Recent studies have shown a role for the Ras guanine exchange factor (RasGEF) Sos1 at the pre-TCR checkpoint. At the second checkpoint, the quality of signaling through the TCR is interrogated to ensure the production of an appropriate T cell repertoire. Although Ras-GRP1 is the only confirmed RasGEF required at the TCR checkpoint, current models suggest that the intensity and character of Ras activation, facilitated by both Sos and RasGRP1, will govern the boundary between survival (positive selection) and death (negative selection) at this stage. Using mouse models, we have assessed the independent and combined roles for the RasGEFs Sos1, Sos2, and RasGRP1 during thymocyte development. Although Sos1 was the dominant RasGEF at the pre-TCR checkpoint, combined Sos1/RasGRP1 deletion was required to effectively block development at this stage. Conversely, while RasGRP1 dele-tion efficiently blocked positive selection, combined RasGRP1/Sos1 deletion was required to block negative selection. This func-tional redundancy in RasGEFs during negative selection may act as a failsafe mechanism ensuring appropriate central tolerance. T cell development is initiated when immature precursor cellsemigrate from the fetal liver or adult bone marrow to the thy-mus. In the thymus, these cells undergo a receptor-driven differ-entiation program, passing through at least two distinct develop-mental checkpoints before emerging as functional T lymphocyte