Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8+ T Cells in Mice With Colitis

Abstract

Background & Aims Tumor necrosis factor (TNF) receptor 2 (TNFR2, Tnfrsf1b) regulates multiple aspects of immune function; but little is known about its role in the immunopathogenesis of inflammatory bowel disease (IBD). We investigated whether TNFR2 restricts the activity of specific immune cell subtypes to protect against the development of colitis in mice. Methods Tnfr2−/− mice were crossed with Il10−/− mice, which spontaneously develop colitis, to generate Il10−/−Tnfr2−/− mice. Colonic tissues were collected from Il10−/−Tnfr2−/− mice along with Il10−/− mice (controls), and analyzed by flow cytometry and histology. Bone marrow was transplanted into Il10−/− and Il10−/−Tnfr2−/− mice from Il10−/− or Il10−/−Tnfr2−/− donors by intravenous injection. CD8+ T cells were neutralized in Il10−/−Tnfr2−/− mice by intraperitoneal injection of anti- CD8 or isotype control antibodies. Colitis was induced in Rag2−/− mice by intravenous injections of naïve CD8+ T cells isolated from C57BL/6 or Tnfr2−/− mice. Results Il10−/−Tnfr2−/− mice spontaneously developed more severe colitis compared to Il10−/− controls, characterized by selective expansion of colonic CD8+ T cells. Transplant of TNFR2- deficient bone marrow resulted in significantly increased incidence and severity of colitis. Transcriptome analyses showed that the expression of genes regulated by TNFR2 were specific to CD8+ T cells, and included genes associated with risk for IBD. Depletion of CD8+ T cells from Il10−/−Tnfr2−/− mice prevented colonic inflammation. Adoptive transfer of TNFR2-null naïve CD8+ T cells, compared with CD8+ T cells from control mice, increased the severity of colitis that developed in Rag2−/− mice. Conclusion TNFR2 protects mice from colitis by inhibiting the expansion of colonic CD8+ T cells. TNFR2 regulates expression of genes that regulate CD8+ T cells and have been associated with susceptibility to IBD. Disruption in TNFR2 signaling might therefore be associated with pathogenesis. Strategies to increase levels or activity of TNFR2, and thereby reduce the activity of CD8+ T cells, might be developed to treat IBD patients with CD8+ T cell dysfunction.

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

“…To this end, mouse strains with genetic ablation of TNFR1 or TNFR2 have been extensively studied in different mouse colitis models. Current studies yielded conflicting results and were thus inconclusive5354555657. For example, Wang and colleagues reported that in an acute colitis model induced by instillation of dextran sulfate sodium (DSS), mice deficient in TNFR1 showed exacerbation of colitis, while deficiency of TNFR2 resulted in markedly reduced inflammation56.…”

“…For example, Wang and colleagues reported that in an acute colitis model induced by instillation of dextran sulfate sodium (DSS), mice deficient in TNFR1 showed exacerbation of colitis, while deficiency of TNFR2 resulted in markedly reduced inflammation56. However, Punit and colleagues reported that TNFR2 deficiency resulted in a greater colitis in il10 −/− mice as well as in mouse colitis induced by AOM/DSS treatment57.…”

Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

“…Expression of TXK, a member of the Tec family of non-receptor tyrosine kinases, in Th1 T cells is obligatory for the production of interferon gamma44. CD8 + T cells have an established role in IBD pathogenesis284546 with recent data suggesting that CD8 + T cell exhaustion may be a critical prognostic factor in immune-mediated diseases47.…”

ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation

“…59 For population analysis experiments, cells were fixed with 4% formaldehyde followed by permeabilization with 0.01% saponin. Cells were incubated with FcBlock (BD Biosciences, 553142, 1:100) for 15 min in FACS buffer (PBS+1% heat-inactivated FBS), followed by incubation for 30 min with the following fluorophore pre-conjugated antibodies: Ly6G FITC (Life Technologies, A25990, 1:100), F4/80-Alexafluor 488 (Life Technologies, MF48020, 1:100), CD11b-APC (Life Technologies, RM2805, 1:100), and Ly6C-BV421 (BD Biosciences, 562727, 1:100).…”