Friday, May 3, 2024
5/3/2024
ABSTRACT Viruses that successfully evade clearance without killing the host establish chronic infection. However, unresolved low-grade inflammation causes morbidity over time, including development of cancers. How to appropriately modulate immune responses to chronic infection without further damaging the host represents a major clinical challenge. Type-17 immunity is invoked by extracellular bacteria and fungi to control resident microbiota and invading pathogens at barrier surfaces, and to promote tissue repair. Th17 cells have received much attention as drivers of inflammation in chronic autoimmune diseases. However, there are sparse data regarding the role of type-17 responses in response to viral infection. Here we have employed the well-characterized model infection, LCMV clone 13, to test the role of IL-17 during chronic viral infection. IL-17 was increased systemically during the switch to the chronic phase of infection. Using genetic and antibody-mediated blockade of IL-17, our data unexpectedly reveal that IL-17 regulates Th1 and CD8+ T cell activation, exhaustion and immunopathology during LCMV infection. We have identified lymphoid stromal cells known as fibroblastic reticular cells (FRC) as key intermediaries of IL-17 effects in secondary lymphoid tissues. Gene expression analysis and antibody-mediated blockade support a role for excess IFNg in driving T cell exhaustion and immunopathology. These unexpected findings lead to our central hypothesis that IL-17 has an immunoregulatory role during chronic infection by limiting antiviral T cell IFNg-mediated exhaustion and immunopathology. This project is designed to dissect the key elements that we have identified to be required in this unexplored immunoregulatory pathway in chronic infection by probing the source of critical IL-17 (aim 1), LN stromal cells as targets of IL-17 (aim 2) and IFNg-mediated effects on exhaustion and immunopathology in absence of IL-17 signaling (aim 3). Together these data will define a novel and previously unexplored axis operating through IL-17 signaling in stromal cells to regulate IFNg- mediated pathology, revealing new opportunities for future therapeutic intervention in chronically infected people.
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