Persistent enteric murine norovirus infection is associated with functionally suboptimal virus-specific CD8 T cell responses (P3187)

Abstract

Abstract Norovirus (NV) gastroenteritis is a major contributor to global morbidity and mortality, yet little is known about immune mechanisms leading to NV control. Previous studies using the murine norovirus (MNV) model have established a key role for T cells in MNV clearance. Despite these advances, important questions remain regarding the magnitude, location, and dynamics of the MNV-specific T cell response. To address these questions, we identified MNV-specific MHC class I immunodominant epitopes by conducting an overlapping peptide screen. Using MHC class I-peptide tetramers, we tracked MNV-specific CD8 T cells in lymphoid and mucosal sites during infection with two strains with distinct biological behavior: acutely-cleared CW3 and persistent CR6. Here, we show that enteric MNV infection elicited robust T cell responses primarily in the intestinal mucosa, and that MNV-specific T cells dynamically regulated the expression of surface molecules associated with activation, differentiation, and homing. Furthermore, compared to MNV-CW3, chronic infection with MNV-CR6 resulted in fewer and less functional CD8 T cells. Finally, MNV-specific CD8 T cells were capable of reducing viral load in persistently infected Rag1-/- mice, consistent with a crucial role for these cells in vivo. Collectively, these data provide fundamental new insights into the adaptive immune response to NV and bring us closer to understanding the correlates of protective antiviral immunity in the intestine.