Interferon gamma promotes long term retention of tissue resident memory T cells in the brain following alphavirus clearance in mice

Abstract

Abstract The prototypic alphavirus Sindbis virus (SINV) targets neurons in mice, providing a well characterized model of alphavirus encephalomyelitis. SINV clearance from the brain requires a noncytolytic mechanism to avoid neurological damage and dysfunction and is facilitated by synergistic cooperation between anti-SINV antibody and interferon gamma (IFN-γ). While infectious virus is cleared from the brain by 7 to 10 days post infection (DPI), SINV RNA levels decrease slowly and remain detectable at low levels for at least a year following infection. Because alphaviral RNA is infectious, strict control by the immune system is required to prevent virus reactivation and relapse of disease. To characterize the long-term T cell response following clearance of infectious virus, C57BL/6 mice with intact or impaired IFN-γ signaling were infected with the nonfatal TE strain of SINV, and the frequency and functionality of different T cell populations were evaluated in the brain by flow cytometry. While highly proliferative short-lived T effector cells made up the majority of CD4+ and CD8+ T cells during active infection at 7 DPI, long-lived effector memory T cells became the predominant T cell type by 14 DPI. Following the period of virus clearance, both CD4+ and CD8+ T cell polyfunctionality increased, with more cells expressing multiple effector proteins at higher intensities, and PD-1 and TIM-3 exhaustion marker expression decreased. The percentage of CD8+ T cells characterized as CD103+ tissue resident memory (TRM) cells was decreased in mice with impaired IFN-γ signaling. This indicates IFN-γ signaling promotes the development of TRM cells in the brain during SINV infection and suggests IFN-γ supports long term control of SINV reactivation.