Inhibitory role of β-arrestin2 in T cells protects against colitis. (MUC2P.823)

Abstract

Abstract β-arrestins have shown to be important regulators of inflammation. The aim of this study was to determine the role of β-arrestin2 in intestinal inflammation. In response to DSS-induced colitis, β-arrestin2 knockout (KO) mice exhibit greater body weight loss, higher disease activity index, shortened colon and loss of thymic weight as compared to wild type (WT) mice. Additionally, number of CD4+T cells and proportion of IL-17A+ (and RORγT+) and IFNγ+ CD4+ T cells were markedly higher in DSS-treated KO colonic lamina propria (cLP). Surprisingly, control KO mice too had higher number of CD4+ T cells and il17a mRNA expression in colon tissue compared to control WT mice. Furthermore, T-cell receptor (TCR) stimulation of MLN and splenic cells led to significantly higher production of IFNγ and IL-17 from KO compared to WT cells. Additionally, naïve CD4+ T cells from KO mice produced higher IFNγ and IL-17 and differentiated into Th1 and Th17 cells to a greater extent following TCR stimulation. These results suggest that the KO colon is likely predisposed to exacerbated mucosal inflammation by virtue of enhanced CD4+ T cell numbers and function. This overt response however, was independent of microbiota since, KO animals co-housed with WT mice also exhibited higher weight loss and colon shortening following DSS. Together, our results demonstrate that β-arrestin2 negatively regulates T cell activation and thereby modulates mucosal response under both basal and inflammatory conditions.