Effector T Cells Boost Regulatory T Cell Expansion by IL-2, TNF, OX40, and Plasmacytoid Dendritic Cells Depending on the Immune Context

Baeyens, Audrey; Saadoun, David; Billiard, Fabienne; Rouers, Angéline; Grégoire, Sylvie; Zaragoza, Bruno; Grinberg‐Bleyer, Yenkel; Marodon, Gilles; Piaggio, Eliane; Salomon, Benoı̂t L.

doi:10.4049/jimmunol.1400504

Cited by 37 publications

(29 citation statements)

References 49 publications

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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

100

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

100

103

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“…T reg cells normally stay at a relatively constant abundance within the CD4 + T-cell population, and expand concomitantly with effector/memory T cells to preserve immune homeostasis during inflammation24. Although not altered at early ages, the percentages of peripheral T reg cells among CD4 + T-cell populations continuously dropped to ∼3% by 4 weeks of age when the mice became moribund (Fig.…”

Section: Resultsmentioning

confidence: 96%

Lkb1 maintains Treg cell lineage identity

Luo

Guo

et al. 2017

Nat Commun

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Regulatory T (Treg) cells are a distinct T-cell lineage characterized by sustained Foxp3 expression and potent suppressor function, but the upstream dominant factors that preserve Treg lineage-specific features are mostly unknown. Here, we show that Lkb1 maintains Treg cell lineage identity by stabilizing Foxp3 expression and enforcing suppressor function. Upon T-cell receptor (TCR) stimulation Lkb1 protein expression is upregulated in Treg cells but not in conventional T cells. Mice with Treg cell-specific deletion of Lkb1 develop a fatal early-onset autoimmune disease, with no Foxp3 expression in most Treg cells. Lkb1 stabilizes Foxp3 expression by preventing STAT4-mediated methylation of the conserved noncoding sequence 2 (CNS2) in the Foxp3 locus. Independent of maintaining Foxp3 expression, Lkb1 programs the expression of a wide spectrum of immunosuppressive genes, through mechanisms involving the augmentation of TGF-β signalling. These findings identify a critical function of Lkb1 in maintaining Treg cell lineage identity.

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“…Probably, a dual effect as observed in T cell subpopulations could be attributed to the ligation strength of OX40, as high concentrations of the anti-hOX40 antibody decreases T reg suppressive function and cell numbers preferentially but maintains the proliferation of naive and memory T cells that become resistant to suppression by T regs [100]. In addition, ligation of OX40 from T regs with OX40L on T cons partially boosts the T reg survival capacity in low inflammation conditions, where other factors such as TNF and plasmacytoid DCs could act to help T reg activation in such conditions [101]. Furthermore, in highly inflammatory conditions OX40 seems to mediate T reg accumulation in the colon and peripheral lymphoid organs [102].…”

Section: Ox40 (Cd134)mentioning

confidence: 99%

Phenotypical characterization of regulatory T cells in humans and rodents

Rodríguez‐Perea

Arcia

Rueda

et al. 2016

Clinical and Experimental Immunology

146

122

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SummaryRegulatory T cells (T regs ) constitute a fascinating subpopulation of CD4 1 T cells due to their ability to limit the immune response against self and non-self antigens. Murine models and antibodies directed against surface and intracellular molecules have allowed elucidation of the mechanisms that govern their development and function. However, these markers used to their classification lack of specificity, as they can be expressed by activated T cells. Similarly, there are slight differences between animal models, in steady state and pathological conditions, anatomical localization and strategy of analysis by flow cytometry. Here, we revised the most common markers utilized for T reg typification by flow cytometry such as CD25, forkhead box protein 3 (FoxP3) and CD127, along with our data obtained in different body compartments of humans, mice and rats. Furthermore, we revised and determined the expression of other molecules important for the phenotypical characterization of T reg cells. We draw attention to the drawbacks of those markers used in chronic states of inflammation. However, until a specific marker for the identification of T regs is discovered, the best combination of markers will depend upon the tissue or the degree of inflammation from which T regs derive.

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Effector T Cells Boost Regulatory T Cell Expansion by IL-2, TNF, OX40, and Plasmacytoid Dendritic Cells Depending on the Immune Context

Cited by 37 publications

References 49 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

Lkb1 maintains Treg cell lineage identity

Phenotypical characterization of regulatory T cells in humans and rodents

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