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

Abdallah Elkhal,Miguel A De La Fuente,Stefan G Tullius,Felix Krenzien,Timm Heinbokel,Midas Seyda,Ionita Ghiran,Virginia Camacho,Hirofumi Uehara,Markus Quante,Hector Rodriguez Cetina Biefer,Jeroen M Schuitenmaker

doi:10.1038/srep22325

Abdallah Elkhal, Miguel A De La Fuente + Show 10 more

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https://doi.org/10.1038/srep22325

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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.

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Been reported in mouse and human experiments[9]
These results demonstrate that NAD+ induces the conversion of CD4+ CD25+ EGFP+ Foxp3+ into CD4+ IL-17A producing T cells in the absence of exogenous TGF-β, IL-6 and IL-23, cytokines previously considered necessary for Th17 activation, proliferation and maintenance[21], and in the presence of IL-2, a Th17 inhibitory cytokine[25]
Our results indicated that Tregs from STAT3−/− mice had a significantly decreased frequency of IL-17A+ cells with a reduced IL-17A production (Fig. 3c) suggesting that NAD+ induces the conversion of Tregs into Th17 cells, at least in part, through the transcription factor STAT3

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Tr1 cells have been shown to have the capacity to co-produce IFNγ and IL-1010. It is well established that IFNγ -producing cells that co-express IL-10 have immunoregulatory properties that have the capacity to inhibit inflammation, promote transplant tolerance and prevent tissue damage[11]. A recent study has shown the importance of CD25 expression levels for the differentiation of CD4+ CD25+ Foxp3+ Tregs into Th17 cells[11]. Our study demonstrates that NAD+ favors the conversion of CD4+ CD25+ Foxp3+ Tregs into IL-17A producing cells through purinergic signaling that involves the transcription factor STAT-3. Our study underscores a robust and unique immunoregulatory property of NAD+ with broad anti-inflammatory and immunosuppressive capacities with a wide spectrum of potential clinical applications

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