T Cell-Intrinsic Interferon Regulatory Factor 1 Expression Suppresses Differentiation of CD4+ T Cell Populations That Support Chronic Gammaherpesvirus Infection.

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with B cell lymphomas. To establish chronic infection, these viruses usurp B cell differentiation and drive a robust germinal center response to expand the latent viral reservoir and gain access to memory B cells. Germinal center B cells, while important for the establishment of latent infection, are also thought to be the target of viral transformation. The host and viral factors that impact the gammaherpesvirus-driven germinal center response are not clearly defined. We show that the global expression of the antiviral and tumor suppressor interferon regulatory factor 1 (IRF-1) selectively attenuates the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and restricts the expansion of the latent viral reservoir. In this study, we found that T cell-intrinsic IRF-1 expression recapitulates some aspects of the antiviral state imposed by IRF-1 during chronic MHV68 infection, including the attenuation of the germinal center response and viral latency in the spleen. We also discovered that global and T cell-intrinsic IRF-1 deficiency leads to an unhindered rise of interleukin-17A (IL-17A)-expressing and follicular helper T cell populations, two CD4+ T cell subsets that support chronic MHV68 infection. Thus, this study unveils a novel aspect of the antiviral activity of IRF-1 by demonstrating IRF-1-mediated suppression of specific CD4+ T cell subsets that support chronic gammaherpesvirus infection. IMPORTANCE Gammaherpesviruses infect over 95% of the adult population, last the lifetime of the host, and are associated with multiple cancers. These viruses usurp the germinal center response to establish lifelong infection in memory B cells. This manipulation of B cell differentiation by the virus is thought to contribute to lymphomagenesis, although exactly how the virus precipitates malignant transformation in vivo is unclear. IRF-1, a host transcription factor and a known tumor suppressor, restricts the MHV68-driven germinal center response in a B cell-extrinsic manner. We found that T cell-intrinsic IRF-1 expression attenuates the MHV68-driven germinal center response by restricting the CD4+ T follicular helper population. Furthermore, our study identified IRF-1 as a novel negative regulator of IL-17-driven immune responses, highlighting the multifaceted role of IRF-1 in gammaherpesvirus infection.