The orphan adapter protein SLY1 as a novel anti-apoptotic protein required for thymocyte development

Background: SH3 containing Lymphocyte Protein (SLY1) is a putative adapter protein exclusively expressed in lymphocytes which is involved in antigen receptor induced activation. We previously have generated SLY1(Delta/Delta) mice harbouring a partial deletion in the N-terminal region of SLY1 which revealed profound immunological defects in T and B cell functions. Results: In this study, T cell development in SLY1(-/-) and SLY1(Delta/Delta) mice was analysed ex vivo and upon cultivation with the bone marrow stromal cell line OP9. SLY1-deficient thymocytes were compromised in inducing nutrient receptor expression and ribosomal protein S6 phosphorylation, indicating a defect in mTOR complex activation. Furthermore, SLY1 was identified as a novel antiapoptotic protein required for developmental progression of T cell precursors to the CD4(+)CD8(+) double-positive stage by protecting from premature programmed cell death initiation in developing CD4-CD8-double-negative thymocytes. In addition, SLY1 phosphorylation was differentially regulated upon Notch ligand-mediated stimulation and expression of the preTCR. Conclusion: Thus, our results suggest a non-redundant role for SLY1 in integrating signals from both receptors in early T cell progenitors in the thymus.