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.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus

“…(23) More importantly, IFN-γ producing cells that co-express IL-10 have displayed immunosuppressive properties. (24) We therefore focused on the effects of TAC on old CD4 + T cells and tested whether the observed prolongation of graft survival in old mice was linked to a modified balance of IFN-γ and IL-10 production by CD4 + T cells. Old and young mice underwent fully MHC-mismatched skin transplants and systemic IFN-γ and IL-10 production was quantified by flow cytometry.…”

“…Of note, double-positive CD4 + IFN-γ + IL-10 + cells also termed regulatory type 1 cells display potent immunosuppressive properties and are able to promote allograft survival independently of CD4 + CD25 + Foxp3 + regulatory T cells. (24) Thus, altering the critical balance of IFN-γ and IL-10 may play a pivotal role in mediating age-specific effects of Tacrolimus. (32,35)…”

NAD+prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages

“…More importantly, WT mice treated with NAD + exhibited 100% survival while casp-11 -/mice treated with PBS exhibited a modest 40% survival, suggesting that NAD + promotes survival beyond non-canonical inflammasome blockade. Our previous studies have delineated the effects of NAD + on various immune cells such as dendritic cells and CD4 + T cells including Th1, Th17, regulatory type 1 (Tr1) and Treg cells communicated exclusively through mast cells (MCs) [15][16][17] . Thereby, NAD + treatment promoted MC derived induction of TR1 cells that resulted into increased systemic levels of IL-10.…”

“…3C). Moreover, we have previously shown that NAD + administration dampens the expression and activation of transcription factors such as STAT-5 16 .…”

“…We have previously delineated immunosuppressive properties of NAD + via a systemic production of IL-10, a robust immunosuppressive cytokine. In addition, we have described the pivotal role of NAD + protecting towards EAE and allograft rejection via an increased frequency of IL-10 producing CD4 + T cells 15,16 . To test if IL-10 plays an additional protective role in the context of NAD + mediated protection towards LPS-induced death, WT mice treated with NAD + or PBS were subjected to intraperitoneal LPS injection (54mg/kg) and IL-10 expression by macrophages, dendritic cells and T cells was assessed 15 hours after LPS administration.…”