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

Housley, William; Adams, Catherine; Nichols, Frank C.; Puddington, Lynn; Lingenheld, Elizabeth G.; Zhu, Li; Rajan, T. V.; Clark, Robert B.

doi:10.4049/jimmunol.1003868

Cited by 98 publications

(88 citation statements)

References 36 publications

(43 reference statements)

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“…[14][15][16]24 Our results extend, in an allo-HCT setting, the observation that Tconvs exert a powerful boost of Treg activity. We also demonstrate for the first time that the sole defect of TNF production by donor T cells was sufficient to completely abolish the Treg suppressive effect in GVHD.…”

Section: Discussionsupporting

confidence: 75%

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

Leclerc

Naserian

Pilon

et al. 2016

Blood

103

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Key Points• In vivo Treg effect depends on TNFa produced by T cells.• TNF/TNFR2 interaction represents a novel immune checkpoint therapy to modulate alloreactivity after allo-HCT. Therapeutic CD41 Foxp3 1 natural regulatory T cells (Tregs) can control experimental graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by suppressing conventional T cells (Tconvs). Treg-based therapies are currently tested in clinical trials with promising preliminary results in allo-HCT. Here, we hypothesized that as Tregs are capable of modulating Tconv response, it is likely that the inflammatory environment and particularly donor T cells are also capable of influencing Treg function. Indeed, previous findings in autoimmune diabetes revealed a feedback mechanism that renders Tconvs able to stimulate Tregs by a mechanism that was partially dependent on tumor necrosis factor (TNF). We tested this phenomenon during alloimmune response in our previously described model of GVHD protection using antigen specific Tregs. Using different experimental approaches, we observed that control of GVHD by Tregs was fully abolished by blocking TNF receptor type 2 (TNFR2) or by using TNF-deficient donor T cells or TNFR2-deficient Tregs. Thus, our results show that Tconvs exert a powerful modulatory activity on therapeutic Tregs and clearly demonstrate that the sole defect of TNF production by donor T cells was sufficient to completely abolish the Treg suppressive effect in GVHD. Importantly, our findings expand the understanding of one of the central components of Treg action, the inflammatory context, and support that targeting TNF/TNFR2 interaction represents an opportunity to efficiently modulate alloreactivity in allo-HCT to either exacerbate it for a powerful antileukemic effect or reduce it to control GVHD. (Blood. 2016;128(12):1651-1659

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Section: Discussionsupporting

confidence: 75%

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

Leclerc

Naserian

Pilon

et al. 2016

Blood

103

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“…There is some evidence that CD120b may mediate some of the pro-Treg functions of tumor necrosis factor-a. For example, tumor necrosis factor-a stimulates Treg proliferation through CD120b (30,31), CD120b signaling stabilizes Tregs in inflammatory environments (31), and expression of CD120b on Tregs is necessary for suppression of colitis (32). GARP is a receptor for latent transforming growth factor-b and can transfer the mature transforming growth factor-b to its receptor on the same cell or another target cell (33).…”

Section: Discussionmentioning

confidence: 99%

A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes

et al. 2016

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Type 1 diabetes (T1D) is caused by immune-mediated destruction of insulin-producing β-cells. Insufficient control of autoreactive T cells by regulatory T cells (Tregs) is believed to contribute to disease pathogenesis, but changes in Treg function are difficult to quantify because of the lack of Treg-exclusive markers in humans and the complexity of functional experiments. We established a new way to track Tregs by using a gene signature that discriminates between Tregs and conventional T cells regardless of their activation states. The resulting 31-gene panel was validated with the NanoString nCounter platform and then measured in sorted CD4+CD25hiCD127lo Tregs from children with T1D and age-matched control subjects. By using biomarker discovery analysis, we found that expression of a combination of six genes, including TNFRSF1B (CD120b) and FOXP3, was significantly different between Tregs from subjects with new-onset T1D and control subjects, resulting in a sensitive (mean ± SD 0.86 ± 0.14) and specific (0.78 ± 0.18) biomarker algorithm. Thus, although the proportion of Tregs in peripheral blood is similar between children with T1D and control subjects, significant changes in gene expression can be detected early in disease process. These findings provide new insight into the mechanisms underlying the failure to control autoimmunity in T1D and might lead to a biomarker test to monitor Tregs throughout disease progression.

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“…Dbc1 does not affect the development of nTreg cells, because the frequency and total number of thymic (24)(25)(26). The effect of the proinflammatory cytokine TNF-α on Treg cells remains controversial (28,29,(40)(41)(42). Grinberg-Bleyer et al (40) showed that TNF-α produced by T effector (Teff) cells boost Treg cells' expansion, whereas Valencia et al (28) reported that TNF-α down-modulated FOXP3 mRNA, FOXP3 protein, and their suppressive function.…”

Section: Discussionmentioning

confidence: 99%

Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

Gao

Tang

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

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Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammationmediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.+ Treg cells are actively engaged in the prevention of autoimmunity and the mitigation of aberrant or excessive immune responses (1-3). The transcription factor Forkhead box P3 (denoted "FOXP3" in humans, and "Foxp3" in mice) is a well-characterized marker of Treg cells, and its expression typically is considered a requisite for Tregcell differentiation and function (4, 5). FOXP3 deficiency leads to the scurfy phenotype in mice and to the immune dysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome in humans (6). Moreover, Treg-cell function is impaired in several autoimmune and inflammatory diseases, including colitis, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (7). Thus, the manipulation of Treg-cell function might provide a practical approach to the treatment of autoimmune and inflammatory diseases.Despite the central role of FOXP3 in Treg cells, many questions remain regarding the molecular mechanisms by which FOXP3 regulates Treg-cell function. Foxp3 protein is expressed transiently in CD4 + CD25− effector T cells upon T-cell receptor (TCR) stimulation but does not generate T cells with suppressive activity (8, 9). It has become evident that Foxp3 alone is insufficient to reproduce completely the differentiation and functional characteristics of Treg cells (10-12). FOXP3 binds with its partners to form multiple positive and negative feedback loops to regulate Treg-cell function subtly (13). FOXP3 interacts with FOXP1 to form heterodimers that promote FOXP3-mediated repression of IL-2 production (14). FOXP3 also binds with several nuclear factors, such as GATA3 (11, 15), RORγt (16), Eos (17), and RUNX1 (18), to drive the Treg cells' genetic program. FOXP3 function also is regulated at the posttranslational level. FOXP3 has been shown to interact with the acetyltransferase Tat-interaction protein 60 kDa (TIP60) to promote FOXP3 acetylation, which is required for Treg cells' suppressive function (19). P300 also regulates (11); therefore, many questions remain regarding the differential modulation of this complex and its effect on Treg-cell differenti...

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

Cited by 98 publications

References 36 publications

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes

Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

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