Disparate roles of SLP‐76 in CD4 T cell effector function and memory generation

The signaling processes coupled to the T cell receptor (TCR) for naïve T cell activation have been well‐characterized; however, the role of TCR signaling intermediates in effector function and memory development remain unknown. To evaluate the role of the linker/adapter protein SLP‐76 in these processes, we used SLP‐76 conditional knockout (SLP76 CKO) mice containing floxed slp76 and a CRE recombinase inducible yfp reporter (SLP‐76 Flox/‐ R26R YFP ). Control yfp reporter mice were treated in parallel as controls for these experiments (CNTRL). CD4 T cells from SLP76 CKO and CNTRL mice were activated in vitro with anti‐CD3/CD28 antibodies, treated with membrane permeable TAT‐fused CRE recombinase to down regulate SLP‐76 expression, analyzed for effector phenotype, and transferred into RAG2 −/− hosts. We found that down regulation of SLP‐76 in primed CD4 T cells did not appreciably alter their activation phenotype or ability to produce IL‐2 and IFNγ in response to TCR/CD3 ligation. However, when transferred into RAG2‐/‐ hosts, slp76 deleted cells persisted in much lower frequencies relative to controls, acquired a CD44 int , CD62L hi central memory phenotype, and were hindered in their long‐term persistence in vivo . These results suggest a differential role for SLP‐76 signaling in effector T cell function relative to naïve and suggest a crucial role for TCR signaling through SLP‐76 in long‐term memory generation.