Rôle des membres de la famille du récepteur au TNF dans la biologie des lymphocytes régulateurs

CD4+ Foxp3+ regulatory T cells (Tregs) play a critical role in immune homeostasis and in the prevention of autoimmune diseases by regulating immune responses, therefore a better knowledge of their biology could improve their use in medicine. Different related molecules compose the large TNF family. Many of their receptors (TNFR family) are expressed by cells of the immune system,specifically byTregs.Blocking or agonist reagents of some TNF or TNFR family members have strong potential to control autoimmune diseases or to improve anti-tumor immunity by acting on conventional T cells or Tregs. However, we know very little on the direct effect of TNFR family members on Treg biology and on similarities and differences of their effects between different members. Here, we showed that Treg co-stimulation with agonists of TNFR2, 4-1BB, GITR or DR3, but not of OX40, increased their proliferation and survival. These co-stimulated Tregs had improved expansion in vivo and increased capacity to control an inflammatory disease. Triggering these receptors induced a similar signature at the transcription level, showing that they share signal transduction. Using a DNA binding assay and loss of function approach, we showed a critical role of the canonical NF-B pathway in the Treg co-stimulation induced by these TNFR family members. Thus, these molecules may play a major role in Treg biology and part of the therapeutic effects of drugs targeting TNF or TNFR family members may be Treg-mediated.Les lymphocytes T régulateurs CD4+ Foxp3+ (Treg) jouent un rôle essentiel dans l'homéostasie du système immunitaire et dans la prévention des maladies auto-immunes. Une meilleure connaissance de leur biologie pourrait améliorer leur utilisation en médecine. Différentes molécules apparentées composent la grande famille du TNF. Beaucoup de leurs récepteurs (famille du TNFR) sont exprimés par les cellules du système immunitaire, en particulier par les Treg. Des molécules agonistes ou inhibitrices de certains membres de la famille du TNF ou du TNFR ont un effet thérapeutique dans les maladies auto-immunes ou les cancers. Leur action pourrait impliquer les Treg. Cependant, nous avons très peu de connaissance sur l’effet direct des membres de la famille TNFR sur la biologie du Treg et sur les similitudes et les différences de leurs effets entre différents membres. Ici, nous montrons que la co-stimulation de Treg par des agonistes de TNFR2, 4-1BB, GITR ou DR3 augmente leur prolifération et leur survie in vitro. Ces Treg co-stimulés ont une expansion améliorée in vivo et une meilleure capacité à contrôler une maladie inflammatoire. L’activation de ces récepteurs induit une signature ARN similaire, suggérant que la transduction du signal est comparable. Enfin, nous montrons le rôle critique de la voie canonique NF-B dans la co-stimulation Treg induite par ces membres de la famille TNFR. Ainsi, ces molécules pourraient jouer un rôle majeur dans la biologie des Treg et une partie des effets thérapeutiques des médicaments ciblant les membres de la famille du TNF ou du TNFR pourrait impliquer les Treg

Tumor necrosis factor receptor family costimulation increases regulatory T‐cell activation and function via NF‐κB

International audienceSeveral drugs targeting members of the TNF superfamily or TNF receptor superfamily (TNFRSF) are widely used in medicine or are currently being tested in therapeutic trials. However, their mechanism of action remains poorly understood. Here, we explored the effects of TNFRSF co-stimulation on murine Foxp3+ regulatory T cell (Treg) biology, as they are pivotal modulators of immune responses. We show that engagement of TNFR2, 4-1BB, GITR, and DR3, but not OX40, increases Treg proliferation and survival. Triggering these TNFRSF in Tregs induces similar changes in gene expression patterns, suggesting that they engage common signal transduction pathways. Among them, we identified a major role of canonical NF-κB. Importantly, TNFRSF co-stimulation improves the ability of Tregs to suppress colitis. Our data demonstrate that stimulation of discrete TNFRSF members enhances Treg activation and function through a shared mechanism. Consequently, therapeutic effects of drugs targeting TNFRSF or their ligands may be mediated by their effect on Tregs

Tumor necrosis factor receptor family costimulation increases regulatory T‐cell activation and function via NF‐κB

International audienceSeveral drugs targeting members of the TNF superfamily or TNF receptor superfamily (TNFRSF) are widely used in medicine or are currently being tested in therapeutic trials. However, their mechanism of action remains poorly understood. Here, we explored the effects of TNFRSF co-stimulation on murine Foxp3+ regulatory T cell (Treg) biology, as they are pivotal modulators of immune responses. We show that engagement of TNFR2, 4-1BB, GITR, and DR3, but not OX40, increases Treg proliferation and survival. Triggering these TNFRSF in Tregs induces similar changes in gene expression patterns, suggesting that they engage common signal transduction pathways. Among them, we identified a major role of canonical NF-κB. Importantly, TNFRSF co-stimulation improves the ability of Tregs to suppress colitis. Our data demonstrate that stimulation of discrete TNFRSF members enhances Treg activation and function through a shared mechanism. Consequently, therapeutic effects of drugs targeting TNFRSF or their ligands may be mediated by their effect on Tregs

Regulatory T Cell Stability and Migration Are Dependent on mTOR

International audienceCD4+ Foxp3+ regulatory T cells (Treg) are essential to maintain immune tolerance, as their loss leads to a fatal autoimmune syndrome in mice and humans. Conflicting findings have been reported concerning their metabolism. Some reports found that Treg have low mechanistic target of rapamycin (mTOR) activity and would be less dependent on this kinase compared with conventional T cells, whereas other reports suggest quite the opposite. In this study, we revisited this question by using mice that have a specific deletion of mTOR in Treg. These mice spontaneously develop a severe and systemic inflammation. We show that mTOR expression by Treg is critical for their differentiation into effector Treg and their migration into nonlymphoid tissues. We also reveal that mTOR-deficient Treg have reduced stability. This loss of Foxp3 expression is associated with partial Foxp3 DNA remethylation, which may be due to an increased activity of the glutaminolysis pathway. Thus, our work shows that mTOR is crucial for Treg differentiation, migration, and identity and that drugs targeting this metabolism pathway will impact on their biology

The NF-κB RelA Transcription Factor Is Critical for Regulatory T Cell Activation and Stability

International audienceRegulatory T cells (Tregs) play a major role in immune homeostasis and in the prevention of autoimmune diseases. It has been shown that c-Rel is critical in Treg thymic differentiation, but little is known on the role of NF-κB on mature Treg biology. We thus generated mice with a specific knockout of RelA, a key member of NF-κB, in Tregs. These mice developed a severe autoimmune syndrome with multi-organ immune infiltration and high activation of lymphoid and myeloid cells. Phenotypic and transcriptomic analyses showed that RelA is critical in the acquisition of the effector Treg state independently of surrounding inflammatory environment. Unexpectedly, RelA-deficient Tregs also displayed reduced stability and cells that had lost Foxp3 produced inflammatory cytokines. Overall, we show that RelA is critical for Treg biology as it promotes both the generation of their effector phenotype and the maintenance of their identity