TULA-family proteins are key to the regulation of T-cell-driven inflammatory responses. (138.13)

Abstract

Abstract The novel TULA family consists of two proteins recently implicated in cellular regulation. TULA-1 is expressed only in lymphoid cells and has been shown to exert a pro-apoptotic effect in T-cells, possibly through its interaction with AIF. TULA-2 is expressed ubiquitously and is an active phosphatase capable of dephosphorylating proteins involved in receptor-mediated signaling. CD4+ T-cells from mice lacking both family members (dKO) are hypersensitive to TCR stimulation. Initial characterization T-cell subpopulations in TULA dKO mice revealed an atypical CD45RB distribution among dKO CD4+ T-cells. Further analysis of memory and regulatory markers indicate that both memory and regulatory T-cell populations are expanded in dKO mice. To determine in vivo consequences of these changes, we utilized two mouse models of inflammation in which T-cells play a key role: trinitrobenzene sulfonic acid (TNBS)-induced colitis and colitis induced by the adoptive transfer of CD45RB-high CD4+ T-cells. Studies utilizing TNBS indicated that TULA dKO mice are more sensitive to colitis as compared to WT mice and that the increased sensitivity is dependent on T-cells. Consistent with these findings, dKO CD45RB-high CD4+ T-cells were significantly more colitogenic than the in WT mice in the transfer colitis model. Taken together, our data suggests that TULA-family proteins are key to the physiological regulation of T-cell reactivity that drives inflammatory responses in the intestine.