NAD+ regulates Treg cell fate and promotes allograft survival via a systemic IL-10 production that is CD4+ CD25+ Foxp3+ T cells independent
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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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NAD+ seems to exhibit immunomodulatory properties, such as influencing T cell polarization.
“NAD+ seems to exhibit immunomodulatory properties, such as influencing T cell polarization112,113”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [113]
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Ehrsam, J. P., Chen, J., Haberecker, M., Arni, S., & İnci, İ. (2023) · Transplantation Direct · doi:10.1097/txd.0000000000001516
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Self-citationβ-Nicotinamide adenine dinucleotide (β-NAD) acts as a bronchodilator
Jurastow, I., Wiegand, S., Rafiq, A., Zakrzewicz, A., Engel, S., Sanna, A., von der Beck, D., Klepetko, W., Hecker, A., Günther, A., et al. (2025) · PLoS ONE · doi:10.1371/journal.pone.0334491
Walter, K. A., Boerger, L., Pietsch, A. P., Gilles, L., Brunnbauer, P., Kamali, C., Hillebrandt, K. H., Iske, J., Pratschke, J., Sauer, I. M., et al. (2026) · Artificial Organs · doi:10.1111/aor.70197
Self-citation
- Authors
- Elkhal, A., Rodriguez Cetina Biefer, H., Heinbokel, T., Uehara, H., Quante, M., Seyda, M., Schuitenmaker, J. M., Krenzien, F., Camacho, V., de la Fuente, M. A., Ghiran, I., & Tullius, S. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Elkhal, Abdallah
- Tullius, Stefan G.
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-03-01
- Volume
- 6
- Issue
- 1
- Pages
- 22325-22325
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4772111
- OpenAlex
- W2290640882
- Cited by
- 46
- References
- 46
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 7 · 2023: 8 · 2022: 3 · 2021: 4 · 2020: 4 · 2018: 4 · 2017: 6 · 2016: 2
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Valladolid Documentary Repository (University of Valladolid) (publishedVersion, other-oa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
- Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
- Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
- Funders
- Fundación Ramón Areces
- Deutsche Forschungsgemeinschaft (KFO-243)
- National Institutes of Health
- Instituto de Salud Carlos III
- National Institute on Aging (R01AG039449)
- National Heart, Lung, and Blood Institute (R01HL096795)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- NAD+, regulatory T cells, Th17 cells, CD25, IL-10, allograft survival, alloimmunity, immune regulation, IL-17A
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Graft Survival, Homeostasis, Humans, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, NAD, CD4 Antigens, Skin Transplantation, Interleukin-10, Mice, Knockout, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Interleukin-2 Receptor alpha Subunit, Th17 Cells, Allografts
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