Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses

The adaptor protein Src homology 2 domain‐containing leukocyte‐specific protein of 76 kDa (SLP‐76) is central to the organization of intracellular signaling downstream of the T‐cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of WT SLP‐76 protein in thymocytes. Here, we show that following tamoxifen‐regulated conditional deletion of SLP‐76, mature, antigen‐inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR‐generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP‐76 are resistant to induction of the CD4⁺ T‐cell‐mediated autoimmune disease experimental autoimmune encephalomyelitis. Altogether, our findings demonstrate the critical role of SLP‐76‐mediated signaling in initiating T‐cell‐directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects.