Knockout of SLy1 decreases double‐negative thymocyte proliferation and protects mice from p53‐induced tumor formation

The lymphocyte‐specific adapter protein SLy1 has previously been identified as indispensable for thymocyte development and T‐cell proliferation and, recently, as a cause of X‐linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in SLy1KO and SLy1d/d mice. As SLy1KO NK cells show increased levels of p53, we focused our research on the interdependency of SLy1 and p53 for thymocyte development. Using RT‐PCR and immunoblot analysis, we observed increased levels of p53 as well as DNA damage response proteins in SLy1KO thymocytes. To test for rescue from SLy1‐induced deficiencies in thymocyte development like reduced thymocyte numbers and reduced DN to DP progression, we generated a mouse model with T cell‐specific p53‐deficiency on an SLy1KO background and analyzed lymphocyte populations in these mice and respective controls. Astonishingly, SLy1KO‐typical deficiencies were retained, showing that SLy1 is mechanistically independent of p53. Studies of apoptosis and proliferation in SLy1KO thymocytes revealed decreased proliferation in the DN3 subpopulation as a possible reason for the decreased thymocyte number. In mice with p53‐deficient T cells, we observed tumor formation leading to reduced survival, preferentially in SLy1WT mice. Thus, we suggest that a SLy1‐deficiency reduces proliferation, resulting in less hematologic tumors initiated by the p53‐deficiency. SLy1‐deficiency leads to an impaired development from double‐negative (DN) to double‐positive (DP) thymocytes resulting in reduced T cells. We observed an upregulation of p53 signaling and an impaired rate of proliferation and apoptosis. In turn, this defect seems to reduce the susceptibility to tumor formation by loss of p53.