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 using an overlapping peptide screen. One of these epitopes (ORF2519-527) was highly conserved among all NV genogroups. Using MHC class I/peptide tetramers, we tracked MNV-specific CD8 T cells in lymphoid and mucosal sites d... More
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 using an overlapping peptide screen. One of these epitopes (ORF2519-527) was highly conserved among all NV genogroups. Using MHC class I/peptide tetramers, we tracked MNV-specific CD8 T cells in lymphoid and mucosal sites during infection with two MNV 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 CD8 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, and this difference was evident as early as day 8 post-infection. Finally, MNV-specific CD8 T cells were capable of reducing viral load in persistently infected Rag1-/- mice, suggesting that these cells are a crucial component of NV immunity. Collectively, these data provide fundamental new insights into the adaptive immune response to two closely-related NV strains with distinct biological behavior and bring us closer to understanding the correlates of protective antiviral immunity in the intestine.
