TULA-family proteins are key to the regulation of T-cell-driven inflammatory response. (50.1)

Abstract

Listen

Translate article

Abstract The TULA-family consists of two proteins implicated in cellular regulation. TULA-1 is expressed in T-cells and is pro-apoptotic. TULA-2 is a ubiquitously expressed phosphatase that suppresses receptor-mediated signaling. T-cells from mice lacking TULA-1 and 2 (dKO) are hypersensitive to TCR stimulation. This may be due to these proteins having a similar function working synergistically or dissimilar functions having a convergent effect. To understand functional interaction of these proteins we have characterized TULA-family knockout mice without and during an immune challenge. We show that CD4+ T cells of dKO mice have an atypical CD45RB distribution, and that within this subset memory T-cells are expanded only in dKO not in single TULA knockouts. However, CD4+ T-cells of single knockout and wild-type mice respond differently to TCR stimulation as seen using signaling and responses in vitro. To evaluate consequences of TULA deficiency in vivo, we utilize two mouse models of inflammatory bowel disease: TNBS-induced colitis and colitis induced by the adoptive transfer of CD45RBHigh CD4+ T-cells. Studies utilizing TNBS indicate that deficiency of any TULA-family protein exacerbates TNBS-induced colitis. Likewise, dKO CD45RBHigh CD4+ T cells were significantly more colitogenic than cells from WT mice in the transfer model. Taken together, our data indicate that TULA-family proteins are key to the physiological regulation of T-cell reactivity that drives intestinal inflammation.