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

Abstract

SUMMARY 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 wild-type SLP-76 protein in thymocytes. 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. 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.

The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation

“…Indeed, such maneuvers can significantly perturb TCR expression as well as peripheral T-cell responses. 17 By using a temporal deletion strategy, we circumvented the developmental abnormalities and examined the effects of SAP deletion in peripheral iNKT cells that were phenotypically similar to normal iNKT cells. Second, these results highlight the importance of Fyn during regulation of immune cell functions.…”

“…weeks to allow for iNKT cell development. Subsequently, mice were fed tamoxifen, 17 rested for 5 to 7 days to allow for degradation of SAP protein, and analyzed for SAP expression and iNKT cell incidence, number, and phenotype (supplemental Figure 1). By using this approach, >95% of lymphocytes, including all YFP 1 iNKT cells, were devoid of SAP protein ( Figure 1A and not shown).…”

Diacylglycerol Kinase ζ Is a Target To Enhance NK Cell Function

“…DGKζ F/F Rosa26-Stop-Flox-YFP ERCreT2 or control Rosa26-Stop-Flox-YFP ERCreT2 mice were treated with Tamoxifen for 5 days as previously described (21). 1 week after the end of treatment, splenocytes were removed for functional analysis.…”

Regulatory T Cells Require TCR Signaling for Their Suppressive Function

“…UBC-CreER T2 used for acute deletion has been described (28). SLP-76 conditional heterozygous (cHet), SLP-76 conditional knockout (cKO), and SLP-76 Y145F mice have been previously described (29, 30). Bcl-xL transgenic mice were a gift from Dr. Craig Thompson (31).…”