Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs

Grinberg‐Bleyer, Yenkel; Saadoun, David; Baeyens, Audrey; Billiard, Fabienne; Goldstein, Jack; Grégoire, Sylvie; Martin, Gaëlle H.; Elhage, Rima; Dérian, Nicolas; Carpentier, Wassila; Marodon, Gilles; Klatzmann, David; Piaggio, Eliane; Salomon, Benoı̂t L.

doi:10.1172/jci42945

Cited by 157 publications

(147 citation statements)

References 58 publications

(69 reference statements)

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“…Signaling through TNFR2 then leads to expansion of regulatory T cells that protect NOD mice from diabetes. Our data are compatible with the recent study showing that blockade of TNF reduced the proliferation of regulatory T cells and that TNF secreted by effector T cells boosted the expansion of regulatory T cells (23). To prove our hypothesis, Table I shows the strain and number of mice in each group that underwent GK1.5 treatment and developed T1D.…”

Section: Discussionsupporting

confidence: 91%

“…One of the effects of TNF-TNFR2 signaling is the promotion of T regulatory cell expansion (22). It has been shown recently that activated autoreactive T effectors secrete TNF-a, which induces an expansion of T regulatory cells via TNF-TNFR2 interactions (23). This is one of the proposed mechanisms for fine tuning the balance between effector T cells and the regulatory T cells to control autoimmune diseases such as multiple sclerosis and diabetes.…”

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confidence: 99%

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TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

Chee

Angstetra

Mariana

et al. 2011

The Journal of Immunology

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TNF has been implicated in the pathogenesis of type 1 diabetes. When administered early in life, TNF accelerates and increases diabetes in NOD mice. However, when administered late, TNF decreases diabetes incidence and delays onset. TNFR1-deficient NOD mice were fully protected from diabetes and only showed mild peri-insulitis. To further dissect how TNFR1 deficiency affects type 1 diabetes, these mice were crossed to β cell-specific, highly diabetogenic TCR transgenic I-Ag7–restricted NOD4.1 mice and Kd-restricted NOD8.3 mice. TNFR1-deficient NOD4.1 and NOD8.3 mice were protected from diabetes and had significantly less insulitis compared with wild type NOD4.1 and NOD8.3 controls. Diabetic NOD4.1 mice rejected TNFR1-deficient islet grafts as efficiently as control islets, confirming that TNFR1 signaling is not directly required for β cell destruction. Flow cytometric analysis showed a significant increase in the number of CD4+CD25+Foxp3+ T regulatory cells in TNFR1-deficient mice. TNFR1-deficient T regulatory cells were functionally better at suppressing effector cells than were wild type T regulatory cells both in vitro and in vivo. This study suggests that blocking TNF signaling may be beneficial in increasing the function of T regulatory cells and suppression of type 1 diabetes.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

Chee

Angstetra

Mariana

et al. 2011

The Journal of Immunology

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“…It has been reported previously that TNFR2 2/2 nTregs are able to suppress normally in vitro (14). In this study, we find no phenotypic differences between WT and TNFR2 2/2 nTregs that would account for the abnormal in vivo function of TNFR2 (19) showing that TNF-a is necessary for optimizing, or "boosting," Treg function in the context of autoimmunity, rather than being required for the baseline functioning of Tregs. Furthermore, TNFR2 2/2 mice demonstrate exacerbated disease when induced to develop experimental autoimmune encephalomyelitis, further suggesting that the anti-inflammatory effects of TNF-a are mediated through TNFR2 (36).…”

Section: Preactivation Of Tnfr2supporting

confidence: 52%

“…Although reports have shown opposite effects of TNF-a on mouse and human Tregs, both mouse and human studies have suggested that TNFR2 is the primary receptor required for these effects. Recently, using murine models of diabetes, Grinberg-Bleyer et al (19) demonstrated that the suppressive function of Tregs is optimized by the presence of Teffs and that TNF-a is one factor involved in this optimization (19,20). In this study, we have investigated the role of TNFR2 on both murine nTregs and iTregs in the in vivo suppression of autoimmunity.…”

mentioning

confidence: 92%

Natural but Not Inducible Regulatory T Cells Require TNF-α Signaling for In Vivo Function

Housley

Adams

Nichols

et al. 2011

The Journal of Immunology

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TNF-α has a multifunctional role in autoimmune diseases as reflected in the variable responses of different human diseases to anti–TNF-α therapy. Recent studies have suggested that TNF-α modulates autoimmunity partially via effects on regulatory T cells (Tregs) and that these effects are mediated through the type II TNFR (TNFR2). We have investigated the requirement for TNFR2-expression on murine natural Tregs (nTregs) and induced Tregs (iTregs) in mediating suppression of colitis. Surprisingly, we find that TNFR2-expression is required for both spleen- and thymus-derived nTreg-mediated suppression, but is not required for iTreg-mediated suppression. Abnormal TNFR2−/− nTreg function was not associated with an in vivo decrease in accumulation, stability, or expression of markers known to be relevant in Treg function. Because iTregs are generated in the presence of TGF-β, we investigated whether activation in the presence of TGF-β could overcome the functional defect in TNFR2−/− nTregs. Although preactivation alone did not restore suppressive function of nTregs, preactivation in the presence of TGF-β did. These results identify potentially critical differences in activation requirements for nTregs versus iTregs. Furthermore, our findings are consistent with reports suggesting that nTregs are activated in sites of inflammation while iTregs are activated in lymph nodes. Finally, by demonstrating that nTregs require TNF-α for optimal function whereas iTregs do not, our results suggest that the enigma of variable responses of different human diseases to anti–TNF-α therapy may relate to whether nTregs or iTregs have the predominant regulatory role in a given disease.

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“…Within these transcripts, the Tnfrsf1b (TNFR2) transcript was most intriguing because TNF-a has recently been shown to promote Treg cell expansion and activation in the inflammatory microenvironment through TNFR2 in an antigen-nonspecific way. 8 Correlating with the gene expression results, by flow cytometric analysis, the CD103 C Treg cells expressed higher levels of TNFR2 when compared with CD103 ¡ Treg cells in spleen (Fig. 4B) and tumor microenvironment (Fig.…”

Section: Cd103supporting

confidence: 58%

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

et al. 2015

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Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8C T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models. Correspondingly, increased levels of TNF-a in both tissue and serum were also demonstrated. Interestingly, TNF-a could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against antitumor immunity of CD8 C T cells. Furthermore, targeting TNFR2 signaling with a TNF-a inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-a could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-a inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion.

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Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs

Cited by 157 publications

References 58 publications

TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

Natural but Not Inducible Regulatory T Cells Require TNF-α Signaling for In Vivo Function

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

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