Investigating the impact of type I IFN signaling on regulatory T cell function during mucosal HSV-2 infection

/ABSTRACT Herpes simplex virus type-2 (HSV-2) is one of the most prevalent sexually transmitted infections, affecting over 400 million people worldwide and nearly twice as many people with XX chromosomes as people with XY chromosomes. HSV-2 causes lifelong, recurrent lesions due to its ability to evade the adaptive immune system and establish latency. Understanding the immune response to early infection before the virus establishes latency can provide valuable insight into therapeutic and vaccine design. Early HSV-2-induced inflammation triggers the production of type I interferons (IFNs) which have broad effects on priming and enhancing the host response. Regulatory T cells (Tregs), an immunosuppressive subset of CD4+ T cells, have been shown to respond to IFN signaling in a systemic viral infection model, whereby IFNs attenuate Treg function to enable a functional, virus-specific effector T cell response. As HSV-2 causes a local infection in the vaginal mucosa, it is unknown how IFN signaling affects Treg function in a more nuanced infection model, especially since we have previously shown that vaginal Tregs are phenotypically distinct from the circulating Tregs that would be involved in a systemic infection. Preliminary data of murine vaginal tract Tregs shows that upon exposure to IFNs, Tregs have decreased expression of suppressive and activation markers. Using a conditional knockout mouse line where the IFNα receptor (IFNAR) is selectively deleted on Tregs, there is a decrease in cytokines and chemokines related to antigen presentation and T cell recruitment. This suggests that IFN signaling in Tregs is necessary to promote antigen-specific T cell activation. We hypothesize that IFN signaling in Tregs is responsible for attenuating Treg suppressive function during the early stages of HSV-2 infection to allow for appropriate antigen presentation and effector T cell priming. The proposed studies will use a combination of phenotypic, functional, and genomic sequencing assays to determine the mechanism by which IFN signaling in Tregs alters Treg suppressive function and the extent to which this impacts HSV-2 immunity in the vaginal mucosa. Project Number: 1F31AI191688-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Lakshmi Warrier | Institution: FRED HUTCHINSON CANCER CENTER, SEATTLE, WA | Award Amount: $49,343 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F07C-H (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI19168801A1