TY - JOUR
T1 - Type I interferons augment regulatory T cell polarization in concert with ancillary cytokine signals
AU - Eskandari, Siawosh K.
AU - Allos, Hazim
AU - Safadi, Jenelle M.
AU - Sulkaj, Ina
AU - Sanders, Jan S.F.
AU - Cravedi, Paolo
AU - Ghobrial, Irene M.
AU - Berger, Stefan P.
AU - Azzi, Jamil R.
N1 - Publisher Copyright:
2023 Eskandari, Allos, Safadi, Sulkaj, Sanders, Cravedi, Ghobrial, Berger and Azzi.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - foxp regulatory t cells
KW - interferon alpha
KW - interferon beta
KW - interleukin
KW - treg induction
KW - type interferons
UR - http://www.scopus.com/inward/record.url?scp=85181228938&partnerID=8YFLogxK
U2 - 10.3389/frtra.2023.1149334
DO - 10.3389/frtra.2023.1149334
M3 - Article
AN - SCOPUS:85181228938
SN - 2813-2440
VL - 2
JO - Frontiers in Transplantation
JF - Frontiers in Transplantation
M1 - 1149334
ER -