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 À/À or WT mice as donors of colitogenic CD4 + CD45RB hi T cells for transfer into syngeneic RAG2 À/À or RAG2 À/À TNFR2 À/À recipient mice. Although the absence of TNFR2 expression by nonlymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2 À/À CD4 + T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2 À/À CD4 1 T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2 À/À CD4 1 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.Key words: CD4 1 T cells Á Inflammation Á Intestinal immunity Á TNF Introduction TNF plays a fundamental role in immunity and inflammation based on its pleiotropic effects on differentiation, growth and apoptotic cell death of both immune and non-immune cell subsets [1,2]. It is well established that TNF is also critically involved in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis, MS and inflammatory bowel diseases (IBD) [3]. Monocytes and macrophages are the main producers of TNF, but T and B lymphocytes and also mast cells can produce significant amounts of TNF. Interestingly, intestinal cell lines are induced to synthesize TNF upon infection with invasive bacterial strains [4]. TNF mediates its functions by binding as a trimer to either TNF receptor (TNFR) 1 or 2. The binding of TNF trimer to the preassembled TNFR complex leads to conformational changes of the receptors facilitating signal transduction through rapid recruitment of downstream signaling molecules. Both receptors have distinct signal transduction pathways and mediate distinct cellular responses [1,[5][6][7][8][9][10]. The 55 kDa receptor, TNFR1 (also known as p55, p60, TNFRSF1a, CD120a) is expressed on most cell types. The intracellular domain of TNFR1 contains a death domain (DD) that leads to apoptosis through caspase activation. TNFR1 signaling can also mediate transcription of anti-apoptotic proteins, inflammatory cytokines and chemokines through activation of NF-kB. The 75 kDa receptor, TNFR2 (also known as p75, p80, TNFRSF1b, CD120b), is Eur. J. Immunol. 2009. 39: 1743-1753 DOI 10.1002 Cellular immune response 1743 expressed predominantly by haematopoietic cells, but expression by other cell types can be i...

PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner

“…10) corresponds with previous reports and supports the concept that TNFR2 plays an important role in various PGRN-mediated pathophysiological conditions. Interestingly, a lack of TNFR2 expression within CD4+ T cells was also reported to exacerbate the development of T cells transfer colitis in mice43. It is noted that Chen and colleagues agreed that PGRN stimulation of regulatory T cells (Treg) was mediated by TNFR2.…”

Targeting tumour necrosis factor receptor 1 assembly reverses Th17-mediated colitis through boosting a Th2 response

“…In a DSS-induced mouse colitis model similar to UC, TNFR1 deficiency accelerated the onset of disease, while TNFR2 knockout attenuated the severity of colitis,35 supporting a protective role of TNFR1 in an innate-mediated colitis. However, transfer of TNFR2 −/− CD45RB hi CD4 T cells into RAG −/− recipients leads to an accelerated onset of disease and more severe signs of inflammation,36 indicating that lack of TNFR2 signalling leads to exacerbation of T-cell-mediated colitis. Moreover, tissue damage scores in TNFR1 −/− mice were lower after TNBS-induced colitis, similar to CD, compared with wild-type or TNFR2 −/− mice,37 suggesting a role of TNFR1 in pathogenesis of a T-cell-dependent colitis.…”

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

“…In agreement with these findings, AICD and contraction of activated, TNFR2-deficient CD4 T cells is impaired, leading to the preferential expansion of TNFR2-deficient CD4 T cells upon co-transfer with wtCD4 T cells into lymphopenic mice. As a consequence, transferred TNFR2-deficient CD4 T cells induce an accelerated onset of colitis in RAG2 À/À mice [39].…”

“…In agreement with these findings, AICD and contraction of activated, TNFR2-deficient CD4 T cells is impaired, leading to the preferential expansion of TNFR2-deficient CD4 T cells upon co-transfer with wtCD4 T cells into lymphopenic mice. As a consequence, transferred TNFR2-deficient CD4 T cells induce an accelerated onset of colitis in RAG2 À/À mice [39].At present, one of the main concerns of a treatment with TNFneutralizing agents is the potentially enhanced risk of opportunistic infections, particularly with M. tuberculosis [40]. As a possible way to circumvent this problem, the use of specific TACE inhibitors has been proposed.…”