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Type I Interferon Disrupts T Cell Development and Differentiation During an Established Persistent Infection


Persistent viral infection places a significant burden on global heath. Pathogens such as human immunodeficiency virus (HIV), and hepatitis B and C are able to replicate at high levels within their host, outpacing the immune response and ultimately leading to its attenuation. This attenuation is largely the result of host-derived suppressive factors produced in response to the chronic inflammation and immune-mediated damage to critical lymphoid organs accrued throughout the course of the immune response itself. The landscape of the persistently infected immune environment is thus profoundly altered from its naïve state, raising the possibility that new CD4 and CD8 T cell responses that develop and differentiate in the midst of persistent infection could function differently than T cell responses in a healthy environment.

Using lymphocytic choriomeningitis virus (LCMV) as a model system of persistent infection, we determined that de novo virus-specific T cell responses primed in the midst of persistent infection are impaired. Virus-specific CD8 T cells primed in the midst of persistent infection assume a terminally differentiated phenotype and form defective peripheral effector memory, while virus-specific CD4 T cell responses fail to generate Th1 immunity, instead becoming almost exclusively T follicular helper cells (Tfh). This alteration in the T cell differentiation pattern was mediated by chronic type I interferon (IFN-I) signaling, and blockade of IFN-I signaling restored normal differentiation. Moreover, we observed that IFN-I signaling in the context of persistent LCMV infection led to profound thymic atrophy and disrupted the development of T cell precursors. Together, our data demonstrate several novel mechanisms by which IFN-I acts to modulate the immune response during persistent viral infection. Moreover, the data suggest that modulation of the IFN-I signaling pathway or its downstream targets could lead to treatments to purge persistent viral infection.

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