Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signals
In the transplant community, research efforts exploring endogenous alternatives to inducing tolerogenic allo-specific immune responses are much needed. In this regard, CD4 + FoxP3+ regulatory T cells (Tregs) are appealing candidates due to their intrinsic natural immunosuppressive qualities. To date...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Transplantation |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/frtra.2023.1149334/full |
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| author | Siawosh K. Eskandari Siawosh K. Eskandari Hazim Allos Jenelle M. Safadi Jenelle M. Safadi Ina Sulkaj Ina Sulkaj Jan S. F. Sanders Paolo Cravedi Irene M. Ghobrial Stefan P. Berger Jamil R. Azzi |
| author_facet | Siawosh K. Eskandari Siawosh K. Eskandari Hazim Allos Jenelle M. Safadi Jenelle M. Safadi Ina Sulkaj Ina Sulkaj Jan S. F. Sanders Paolo Cravedi Irene M. Ghobrial Stefan P. Berger Jamil R. Azzi |
| author_sort | Siawosh K. Eskandari |
| collection | DOAJ |
| description | In the transplant community, research efforts exploring endogenous alternatives to inducing tolerogenic allo-specific immune responses are much needed. In this regard, CD4 + FoxP3+ regulatory T cells (Tregs) are appealing candidates due to their intrinsic natural immunosuppressive qualities. To date, various homeostatic factors that dictate Treg survival and fitness have been elucidated, particularly the non-redundant roles of antigenic CD3ζ/T-cell-receptor, co-stimulatory CD28, and cytokine interleukin (IL-)2 dependent signaling. Many of the additional biological signals that affect Tregs remain to be elucidated, however, especially in the transplant context. Previously, we demonstrated an unexpected link between type I interferons (IFNs) and Tregs in models of multiple myeloma (MM)—where MM plasmacytes escaped immunological surveillance by enhancing type I IFN signaling and precipitating upregulated Treg responses that could be overturned with specific knockdown of type I IFN signaling. Here, we elaborated on these findings by assessing the role of type I IFN signaling (IFN-α and -β) on Treg homeostasis within an alloimmune context. Specifically, we studied the induction of Tregs from naïve CD4 T cells. Using in vitro and in vivo models of murine skin allotransplantation, we found that type I IFN indeed spatiotemporally enhanced the polarization of naïve CD4 T cells into FoxP3+ Tregs. Notably, however, this effect was not independent of, and rather co-dependent on, ancillary cytokine signals including IL-2. These findings provide evidence for the relevance of type I IFN pathway in modulating FoxP3+ Treg responses and, by extension, stipulate an additional means of facilitating Treg fitness via type I IFNs. |
| first_indexed | 2024-04-09T17:41:59Z |
| format | Article |
| id | doaj.art-b50d639c88f04efb89352c7184a93f92 |
| institution | Directory Open Access Journal |
| issn | 2813-2440 |
| language | English |
| last_indexed | 2025-03-21T00:52:57Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Transplantation |
| spelling | doaj.art-b50d639c88f04efb89352c7184a93f922024-08-03T05:17:31ZengFrontiers Media S.A.Frontiers in Transplantation2813-24402023-04-01210.3389/frtra.2023.11493341149334Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signalsSiawosh K. Eskandari0Siawosh K. Eskandari1Hazim Allos2Jenelle M. Safadi3Jenelle M. Safadi4Ina Sulkaj5Ina Sulkaj6Jan S. F. Sanders7Paolo Cravedi8Irene M. Ghobrial9Stefan P. Berger10Jamil R. Azzi11Transplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United StatesDivision of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsTransplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United StatesTransplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United StatesPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesTransplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United StatesGraduate Program in Immunology, Johns Hopkins School of Medicine, Baltimore, MD, United StatesDivision of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsTranslational Transplant Research Center, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York City, NY, United StatesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United StatesDivision of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsTransplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United StatesIn the transplant community, research efforts exploring endogenous alternatives to inducing tolerogenic allo-specific immune responses are much needed. In this regard, CD4 + FoxP3+ regulatory T cells (Tregs) are appealing candidates due to their intrinsic natural immunosuppressive qualities. To date, various homeostatic factors that dictate Treg survival and fitness have been elucidated, particularly the non-redundant roles of antigenic CD3ζ/T-cell-receptor, co-stimulatory CD28, and cytokine interleukin (IL-)2 dependent signaling. Many of the additional biological signals that affect Tregs remain to be elucidated, however, especially in the transplant context. Previously, we demonstrated an unexpected link between type I interferons (IFNs) and Tregs in models of multiple myeloma (MM)—where MM plasmacytes escaped immunological surveillance by enhancing type I IFN signaling and precipitating upregulated Treg responses that could be overturned with specific knockdown of type I IFN signaling. Here, we elaborated on these findings by assessing the role of type I IFN signaling (IFN-α and -β) on Treg homeostasis within an alloimmune context. Specifically, we studied the induction of Tregs from naïve CD4 T cells. Using in vitro and in vivo models of murine skin allotransplantation, we found that type I IFN indeed spatiotemporally enhanced the polarization of naïve CD4 T cells into FoxP3+ Tregs. Notably, however, this effect was not independent of, and rather co-dependent on, ancillary cytokine signals including IL-2. These findings provide evidence for the relevance of type I IFN pathway in modulating FoxP3+ Treg responses and, by extension, stipulate an additional means of facilitating Treg fitness via type I IFNs.https://www.frontiersin.org/articles/10.3389/frtra.2023.1149334/fulltype interferonsinterferon alphainterferon betainterleukinfoxp regulatory t cellstreg induction |
| spellingShingle | Siawosh K. Eskandari Siawosh K. Eskandari Hazim Allos Jenelle M. Safadi Jenelle M. Safadi Ina Sulkaj Ina Sulkaj Jan S. F. Sanders Paolo Cravedi Irene M. Ghobrial Stefan P. Berger Jamil R. Azzi Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signals Frontiers in Transplantation type interferons interferon alpha interferon beta interleukin foxp regulatory t cells treg induction |
| title | Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signals |
| title_full | Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signals |
| title_fullStr | Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signals |
| title_full_unstemmed | Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signals |
| title_short | Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signals |
| title_sort | type i interferons augment regulatory t cell polarization in concert with ancillary cytokine signals |
| topic | type interferons interferon alpha interferon beta interleukin foxp regulatory t cells treg induction |
| url | https://www.frontiersin.org/articles/10.3389/frtra.2023.1149334/full |
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