Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

Abstract

TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4+ T-cell transfer model of colitis using TNFR2-/- or WT mice as donors of colitogenic CD4+CD45RBhi T cells for transfer into syngeneic RAG2-/- or RAG2-/- TNFR2-/- recipient mice. Although the absence of TNFR2 expression by non-lymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2-/- CD4+ T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2-/- CD4+ T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2-/- CD4+ T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.