Summary The intestinal epithelium comprises the body’s largest surface exposed to viruses. However, a role for intraepithelial T lymphocytes in resistance against viral infections remain elusive. By fate-mapping T cells recruited to the murine intestinal epithelium, we observed accumulation of CD4 + T cells after infection with murine norovirus (MNV) or mouse adenovirus type-2 (AdV), but not after reovirus infection. Intraepithelial CD4 + T cells recruited after MNV or AdV infection co-express Ly6A and CCR9, and exhibit T helper 1 and cytotoxic profiles. Although these cells display a diverse TCR repertoire, they conferred protection against AdV and MNV both in vivo and in an organoid co-culture model in an IFN-γ-dependent manner. Ablation of the T cell receptor (TCR) or the transcription factor ThPOK in CD4 + T cells prior to infection prevented viral control, while TCR ablation during infection did not impact viral clearance. These results uncover a protective role for intraepithelial Ly6A + CCR9 + CD4 + T cells against enteric viruses.

Newly recruited intraepithelial Ly6A+CCR9+CD4+T cells protect against enteric viral infection