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NAD(+) regulates Treg cell fate and promotes allograft survival via a systemic IL-10 production that is CD4(+) CD25(+) Foxp3(+)

Authors: Abdallah Elkhal|||Hector Rodriguez Cetina Biefer|||Timm Heinbokel|||Hirofumi Uehara|||Markus Quante|||Midas Seyda|||Jeroen M Schuitenmaker|||Felix Krenzien|||Virginia Camacho|||Miguel A de la Fuente|||Ionita Ghiran|||Stefan G Tullius

Journal: Scientific reports

Publication Type: Journal Article

Date: 2016

DOI: PMC4772111

ID: 26928119

Affiliations:

Affiliations

    Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.|||Flow Cytometry Core Facility, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.|||Instituto de Biología y Genética Molecular, University of Valladolid, Valladolid-47003, Spain.|||Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Ma. 02115, USA.|||Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston-02115, MA, USA.

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.


Chemical List

    CD4 Antigens|||Forkhead Transcription Factors|||Foxp3 protein, mouse|||Interleukin-2 Receptor alpha Subunit|||NAD|||Interleukin-10

Reference List

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