Session Type: Poster Session
Date: Tuesday, June 4, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Despite a growing body of work on type 1 interferon (IFNAR1) signaling, there is a lack of consensus on the immunological properties of type I interferons and most notably their modulation of T-cell responses. In the context of viral infections, IFNAR1 signaling was reported as essential to T-cell-mediated antiviral immunity. Recently, however, we found a non-redundant role of IFNAR1 signaling in driving the expansion of regulatory T cells (TRegs) in patients with worsened progression of multiple myeloma. Here, we report how dose- and time-dependent IFNAR1 signaling results in a spectrum of immunomodulatory effects and altered T-cell responses.
*Methods: In vitro. Splenic CD4+CD25- helper T cells (TH) were isolated and cultured with α-CD3/CD28, +/-IL2, and +/-IFN-β, at varying concentrations and time-points. Wild type C57BL/6 (B6) cells were stimulated for 72 hrs, and analyzed by flow cytometry. In vivo. B6.Rag1-/- mice were transplanted with BALB/c skin and injected with CD3+CD25- B6 T cells and treated five days daily with IFN-ß. Seven days post adoptive transfer, draining lymph node T cells were analyzed by flow cytometry. Statistics. Independent samples two-tailed Student’s t-tests were used.
*Results: In in vitro CD4 TReg induction assays, we observed that IFNAR1 signaling differentially affected the TGF-β-mediated conversion of CD4 T cells to TRegs, notably depending on the strength of interleukin (IL-)2 signaling. Intriguingly, the TReg conversion was suppressed in the absence of IL-2 signaling, while increasing dosages of IL-2 normalized, and ultimately enhanced TReg conversion (P<0.001). The dependence of type 1 interferons on IL-2 is in line with previous findings that the effects of IFNAR1 signaling are enhanced in competitive, cytokine-rich microenvironments. Additionally, we observed an essential role for the chronology of IFNAR1 signaling in determining the T-cell fate. Delayed IFNAR1/IL-2 signaling promoted pro-inflammatory T cell proliferation, compared to synchronous TCR/CD28 and IFNAR1/IL-2 signaling, and more importantly attenuated TReg conversion only in the type I interferon-treated condition (P<0.0001). To harness the regulatory arm of the immune system, we pursued synchronous type I interferon treatment in an in vivo skin transplant model (10,000 U/day IFN-β vs. PBS sham, n=5/group). Seven days post the adoptive transfer of mismatched B6 CD3+ cells, we found a five-fold increase in draining lymph node (DLN) TRegs (P<0.01), along with a 24.8% and 42.6% decrease in DLN effector CD44+CD62L- CD4+ (P<0.05) and CD8+ cells (P<0.05) respectively.
*Conclusions: In all, we describe the importance of dosage and timing to the possible immunomodulatory effects of IFNAR1 signaling, and the therapeutic potential of these agents in mitigating alloimmunity.
To cite this abstract in AMA style:Sulkaj I, Allos H, Eskandari SK, Safadi JM, Choi JY, Dulaijan BSAl, Al-Hussain E, Cai S, Azzi JR. The Immunomodulatory Role of Type I Interferons in Alloimmunity [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/the-immunomodulatory-role-of-type-i-interferons-in-alloimmunity/. Accessed June 29, 2022.
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