Viral impact on autoimmune T cells

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IL-17 producing T cells have been implicated in the pathogenesis of numerous autoimmune diseases including multiple sclerosis. Autoimmune diseases frequently exhibit a cyclical pattern, with periods of quiescent disease followed by exacerbations or flares. The unpredictable onset of disease flares makes it difficult to balance the risk of more effective therapies (which come with significant side-effects) versus the risk of long-term disability that comes with each disease exacerbation. Hence, understanding the mechanisms that trigger flares is a critical unmet need. Recent viral infection is one of the most common clinically associated triggers for autoimmune disease flare. However, this presents a conundrum: viral infection drives a strong interferon response that is known to suppress the induction of a type-17 response. In fact, IFNb is one of the oldest and most widely-use therapies for MS, and successful therapy correlates with reduced Th17 cells in peripheral blood. Similarly, suppression of type-17 responses is thought to contribute to susceptibility of recently influenza-infected lungs to secondary bacterial infections. However, there is a paucity of data on how viral infection directly impacts existing type-17 cells: either innate- type gdT17 that provide immediate defense against bacteria amplify inflammation, or autoimmune memory Th17 cells that can trigger relapse. Our surprising new data prompts our hypothesis that viral infection causes transient loss of bystander type-17 cells, and that subsequent rebound of self-reactive Th17 cells contributes to autoimmune flare. If correct, this explains one mechanism underlying the perplexing connections between viral infection, acute susceptibility to secondary bacterial infection and later post-viral susceptibility to autoimmune disease flare. This hypothesis will be tested in the following specific aims: Aim 1: Determine fate of autoreactive Th17 and bystander resident IL-17+ cells during viral infection Aim 2: Define role of autoimmune Th17 cell reactivation by viral infection in EAE relapse susceptibility. These data will define for the first time the impact and consequences of viral infection on existing IL-17 producing T cells and autoimmune disease flare.