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

ABSTRACT: There is now compelling evidence that TNFR2 is constitutively expressed on CD4(+) Foxp3(+) regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4(+) Foxp3(-) effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR2(-/-) mice into Rag 1(-/-) recipients. Transfer of TNFR2-deficient Teff cells failed to induce full-fledged colitis, unlike WT Teffs. This was due to defective proliferative expansion of TNFR2-deficient Teff cells in the lymphopenic mice, as well as their reduced capacity to express proinflammatory Th1 cytokine on a per cell basis. In vitro, the proliferative response of TNFR2 deficient naïve CD4 cells to anti-CD3 stimulation was markedly decreased as compared with that of WT naïve CD4 cells. The hypoproliferative response of TNFR2-deficient Teff cells to TCR stimulation was associated with an increased ratio of p100/p52, providing a mechanistic basis for our findings. Therefore, this study clearly indicates that TNFR2 is important for the proliferative expansion of pathogenic Teff cells.

SUBMITTER: Chen X

PROVIDER: S-EPMC5013387 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Chen Xin X Nie Yingjie Y Xiao Haitao H Bian Zhaoxiang Z Scarzello Anthony J AJ Song Na-Young NY Trivett Anna L AL Yang De Oppenheim Joost J JJ

Scientific reports 20160907

There is now compelling evidence that TNFR2 is constitutively expressed on CD4(+) Foxp3(+) regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4(+) Foxp3(-) effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR ...[more]

PMID: 27601345

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Project description:BACKGROUND & AIMS:Several studies have shown that signaling via the interleukin 23 (IL23) receptor is required for development of colitis. We studied the roles of IL23, dietary factors, alterations to the microbiota, and T cells in the development and progression of colitis in mice. METHODS:All mice were maintained on laboratory diet 5053, unless otherwise noted. We generated mice that express IL23 in CX3CR1-positive myeloid cells (R23FR mice) upon cyclic administration of tamoxifen dissolved in diet 2019. Diets 2019 and 5053 have minor differences in the overall composition of protein, fat, fiber, minerals, and vitamins. CX3CR1CreER mice (FR mice) were used as controls. Some mice were given antibiotics, and others were raised in a germ-free environment. Intestinal tissues were collected and analyzed by histology and flow cytometry. Feces were collected and analyzed by 16S rDNA sequencing. Feces from C57/Bl6, R23FR, or FR mice were fed to FR and R23FR germ-free mice in microbiota transplant experiments. We also performed studies with R23FR/Rag-/-, R23FR/Mu-/-, and R23FR/Tcrd-/- mice. R23FR mice were given injections of antibodies against CD4 or CD8 to deplete T cells. Mesenteric lymph nodes and large intestine CD4+ cells from R23FR or FR mice in remission from colitis were transferred into Rag-/- mice. CD4+ cells were isolated from donor R23FR mice and recipient Rag-/- mice, and T-cell receptor sequences were determined. RESULTS:Expression of IL23 led to development of a relapsing-remitting colitis that was dependent on the microbiota and CD4+ T cells. The relapses were caused by switching from the conventional diet used in our facility (diet 5053) to the diet 2019 and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota but did not alter levels of IL23 in intestinal tissues compared with mice that remained on the conventional diet. Mesenteric lymph nodes and large intestine CD4+ cells from R23FR mice in remission, but not from FR mice, induced colitis after transfer into Rag-/- mice, but only when these mice were placed on the diet 2019. The CD4+ T-cell receptor repertoire of Rag-/- mice with colitis (fed the 2019 diet) was less diverse than that from donor mice and Rag-/- mice without colitis (fed the 5053 diet) because of expansion of dominant T-cell clones. CONCLUSIONS:We developed mice that express IL23 in CX3CR1-positive myeloid cells (R23FR mice) and found that they are more susceptible to diet-induced colitis than mice that do not express IL23. The R23FR mice have a population of CD4+ T cells that becomes activated in response to dietary changes and alterations to the intestinal microbiota. The results indicate that alterations in the diet, intestinal microbiota, and IL23 signaling can contribute to pathogenesis of inflammatory bowel disease.

Dataset Information

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

Publications

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

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