O032 Timing and magnitude of Type I interferon responses by distinct viral sensors impact CD8 T cell exhaustion and chronic infection

Abstract

Viral infection triggers a Type I Interferon (IFN-I) response in most cells by stimulating sensors that detect viral nucleic acids. Toll-like receptor (TLR) 7/9-equipped plasmacytoid dendritic cells (pDCs) are specialized IFN-I-producing cells that are capable of secreting large amounts of IFN-I. IFN-I is also produced by infected cells through RIG-I like receptors (RLR) such as Melanoma Differentiation-Associated Gene 5 (MDA5). While it has been established that IFN-I is critical for the generation of CD8 T cell responses, the impact of disparate sources and signaling pathways of IFN-I during this process remains poorly understood. To more precisely define the role of IFN-I on the generation of antiviral CD8 T cell responses, we chose to study acute and chronic lymphocytic choriomeningitis virus (LCMV) infections in the mouse. WT, BDCA2-DTR, MDA5−/− as well as various TLR-deficient mice were infected with acute or chronic strains of LCMV. Serum IFN-α, antiviral CD8 T cell responses and viral burden were determined at various time points post-infection. We found that while pDC depletion had an early impact on the IFN-I response, it did not affect CD8 T cell responses. However, MDA5 was the key source of IFN-I required for anti-LCMV CD8 T cell responses. During acute infection, the CD8 T cell response relied on CD4 T cell help in the absence of MDA5, while CD8 T cell exhaustion and persistent infection ensue in the absence of both MDA5 and CD4 T cells. Moreover, we found that chronic LCMV infection rapidly attenuated the IFN-I response while early administration of exogenous IFN-I rescued the CD8 T cell response promoting viral clearance. We conclude that induction of effective antiviral CD8 T cells depends on the timing and magnitude of the IFN-I response. IFN-I production by pDCs is too little and too transient to facilitate CD8 T cell responses to LCMV. The magnitude and duration of MDA5-induced IFN-I is adequate to elicit effective CD8 T cell responses and control infection during acute, but not chronic infection, which replicates more rapidly and impairs both MDA5 and CD4 T cell function.Thus, timely administration of exogenous IFN-I may rescue CD8 T cell functions during human chronic viral infections.