title: NAD(+) regulates Treg cell fate and promotes allograft survival via a systemic IL-10 production that is CD4(+) CD25(+) Foxp3(+) T cells independent.
abstract: CD4(+) CD25(+) Foxp3(+) Tregs have been shown to play a central role in immune homeostasis while preventing from fatal inflammatory responses, while Th17 cells have traditionally been recognized as pro-inflammatory mediators implicated in a myriad of diseases. Studies have shown the potential of Tregs to convert into Th17 cells, and Th17 cells into Tregs. Increasing evidence have pointed out CD25 as a key molecule during this transdifferentiation process, however molecules that allow such development remain unknown. Here, we investigated the impact of NAD(+) on the fate of CD4(+) CD25(+) Foxp3(+) Tregs in-depth, dissected their transcriptional signature profile and explored mechanisms underlying their conversion into IL-17A producing cells. Our results demonstrate that NAD(+) promotes Treg conversion into Th17 cells in vitro and in vivo via CD25 cell surface marker. Despite the reduced number of Tregs, known to promote homeostasis, and an increased number of pro-inflammatory Th17 cells, NAD(+) was able to promote an impressive allograft survival through a robust systemic IL-10 production that was CD4(+) CD25(+) Foxp3(+) independent. Collectively, our study unravels a novel immunoregulatory mechanism of NAD(+) that regulates Tregs fate while promoting allograft survival that may have clinical applications in alloimmunity and in a wide spectrum of inflammatory conditions.
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Elkhal
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich-8006, Switzerland.
authors.forename: Hector
authors.initials: H
authors.lastname: Rodriguez Cetina Biefer
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin-10117, Germany.
authors.forename: Timm
authors.initials: T
authors.lastname: Heinbokel
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Quante
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.
authors.forename: Midas
authors.initials: M
authors.lastname: Seyda
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.
authors.forename: Jeroen M
authors.initials: JM
authors.lastname: Schuitenmaker
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Krenzien
authors.affiliation: Flow Cytometry Core Facility, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Camacho
authors.affiliation: Instituto de Biología y Genética Molecular, University of Valladolid, Valladolid-47003, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: de la Fuente
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Ma. 02115, USA.
authors.forename: Ionita
authors.initials: I
authors.lastname: Ghiran
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Tullius
mesh_terms: D064591:Allografts / Q000637:transplantation; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006085:Graft Survival / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009243:NAD / Q000627:therapeutic use*; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D009243:NAD; D016753:Interleukin-10