title: Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells.
abstract: Therapeutic CD4(+)Foxp3(+) 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.
authors: Université Paris-Est, Unité mixte de recherche S955, Université Paris Est Créteil, Créteil, France; INSERM, U955, Equipe 21, Créteil, France;
authors: Mathieu
authors: M
authors: Leclerc
authors: Université Paris-Est, Unité mixte de recherche S955, Université Paris Est Créteil, Créteil, France; INSERM, U955, Equipe 21, Créteil, France;
authors: Sina
authors: S
authors: Naserian
authors: Université Paris-Est, Unité mixte de recherche S955, Université Paris Est Créteil, Créteil, France; INSERM, U955, Equipe 21, Créteil, France; Assistance Publique Hôpitaux de Paris (APHP), Hôpital H. Mondor-A. Chenevier, Centre d'Investigation Clinique Biothérapie, Créteil, France;
authors: Caroline
authors: C
authors: Pilon
authors: Université Paris-Est, Unité mixte de recherche S955, Université Paris Est Créteil, Créteil, France; INSERM, U955, Equipe 21, Créteil, France;
authors: Allan
authors: A
authors: Thiolat
authors: Université Paris-Est, Unité mixte de recherche S955, Université Paris Est Créteil, Créteil, France; INSERM, U955, Equipe 21, Créteil, France;
authors: Gaëlle H
authors: GH
authors: Martin
authors: Sorbonne Universités, UPMC Université Paris 06, INSERM, Centre Nationale de la Recherche Scientifique, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France;
authors: Charlotte
authors: C
authors: Pouchy
authors: APHP, Hôpital H. Mondor-A. Chenevier, Service d'oncologie-radiothérapie, Créteil, France;
authors: Claude
authors: C
authors: Dominique
authors: Université Paris-Est, Unité mixte de recherche S955, Université Paris Est Créteil, Créteil, France; APHP, Hôpital H. Mondor-A. Chenevier, Service d'oncologie-radiothérapie, Créteil, France;
authors: Yazid
authors: Y
authors: Belkacemi
authors: APHP, Hôpital Pitié-Salpêtrière, Service d'anatomo-pathologie, Paris, France; and.
authors: Frédéric
authors: F
authors: Charlotte
authors: Université Paris-Est, Unité mixte de recherche S955, Université Paris Est Créteil, Créteil, France; INSERM, U955, Equipe 21, Créteil, France; APHP, Hôpital H. Mondor-A. Chenevier, Service d'hématologie clinique, Créteil, France.
authors: Sébastien
authors: S
authors: Maury
authors: Sorbonne Universités, UPMC Université Paris 06, INSERM, Centre Nationale de la Recherche Scientifique, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France;
authors: Benoit L
authors: BL
authors: Salomon
authors: Université Paris-Est, Unité mixte de recherche S955, Université Paris Est Créteil, Créteil, France; INSERM, U955, Equipe 21, Créteil, France; Assistance Publique Hôpitaux de Paris (APHP), Hôpital H. Mondor-A. Chenevier, Centre d'Investigation Clinique Biothérapie, Créteil, France;
authors: José L
authors: JL
authors: Cohen
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha