Regulation of CD4+ and CD8+ Effector Responses by Sprouty-1

Abstract

TCR-induced NF-AT activation leads to the expression of both activating and inhibitory proteins. Previously, we had identified Egr-2 and Egr-3 as NF-AT-induced transcription factors which promote the inhibition of T cell activation. In this report we identify Sprouty1 as a downstream target of Egr-3. CD4+ T cells lacking Spry1 demonstrate enhanced proliferation and cytokine production. Likewise, Spry1Flox/Flox Lck Cre CD8+ T cells display increased cytolytic activity. Mechanistically, Spry1 acts at the level of PLC-γ promoting the inhibition of both Ca++ induced NF-AT activation and MAP-kinase induced AP-1 activation while sparing NF-κB signaling. In vivo, mice in which Spry1 is selectively deleted in T cells demonstrate enhanced responses to a tumor vaccine and subsequently reject tumors more robustly than Wt mice. These findings suggest that targeting Spry1 might prove to be a novel means of enhancing tumor immunotherapy. © 2012 Collins et al.