The effect of type I interferon on infection and the CD8 T cell response to Coxsackievirus B3 2255932

Abstract

Abstract Introduction Coxsackievirus B3 (CVB3) is the leading cause of viral myocarditis, which disproportionately affects males in both humans and mice. Sex-specific immune responses likely contribute to this bias; however, the mechanisms remain unclear. We previously found that CVB3 induced expansion of protective CD8 T cells in female but not male Ifnar-/- mice. To further define this difference, we evaluated how type I interferon (IFN) influences infection and CD8 T cell responses to CVB3. Furthermore, we bioinformatically predicted CVB3 CD8 T cell epitopes to track these T cell responses. Methods Beta-2-microglobulin knockout (b2M-/-) and bone marrow chimera were intraperitoneally inoculated with 1x104 PFUs of CVB3. Bone marrow chimera mice were prepared by lethal irradiation of male and female Ifnar-/- mice, followed by reconstitution of their immune cells with bone marrow from sex-matched Ifnar-/- and wild-type mice. Splenic T cells were evaluated by flow cytometry, and mice were monitored for survival. Finally, NetMHCcons, PickPocket, and Consensus algorithms were used to predict CD8 T cell epitopes of CVB3. Results We found that CVB3-inoculated female β2M-/- mice, which lack CD8 T cells but exhibit an IFN response, had significantly more CVB3-induced mortality than wild-type mice. Furthermore, to evaluate the contribution of type I IFN on the CD8 T cell response, we found that bone marrow chimera mice that received either Ifnar-/- or wild-type immune cells showed similar responses in CD8 T cells to CVB3 infection. Finally, since CD8 T cell epitopes for CVB3 have not been identified, we employed a bioinformatic approach to identify 33 top candidates that map across the CVB3 genome. Conclusion Overall, these data indicate that CVB3-specific CD8 T cells offer immune protection in female mice, independent of type I IFNs. We are currently confirming the CD8 T cell epitopes so we can track the fate of these CD8 T cells to determine their long-term protection against CVB3 infection. Funding Source K01: DK110216, R03: DK124749, a Biomedical Research Grant from the Indiana Clinical and Translational Sciences Institute, and an American Heart Association (grant 23TPA1141316) to CMR. Topic Categories Viral Immunology (VIR)