Enteric infection of mice with respiratory enteric orphan virus (reovirus) type 1, strain Lang elicits both humoral and cellular immune responses. To investigate the role of CD8+, alpha/beta T-cell receptor (TCR)+ T cells in mucosal immunity to an enteric pathogen, we examined immune responses and viral clearance following enteric reovirus infection in C57BL/6, B6129F2, and beta2-microglobulin-deficient (beta2m-/-) mice. Analysis of Peyer's patch and lamina propria culture supernatants revealed a two- to threefold increase in levels of reovirus-specific immunoglobulin A in beta2m-/- mice compared to normal controls. These data corresponded to a similar increase in the frequency of virus-specific immunoglobulin A-producing cells in Peyer's patches and lamina propria and an increase in immunoglobulin G-producing cells in spleens from beta2m-/- mice compared to controls. These increased humoral immune responses were not due to a difference in B-cell populations because cell counts and flow cytometric analyses showed that beta2m-/- and control mice had similar numbers and percentages of B cells in mucosal and systemic tissues. Analysis of cytokine message by reverse transcriptase-PCR 5 and 10 days after infection revealed no difference in message level for transforming growth factor beta, gamma interferon, interleukin-4, interleukin-5, or interleukin-6 for all mouse strains. Virus tissue titers determined by plaque assay at 5 and 10 days after infection demonstrated that beta2m-/- mice cleared reovirus from the small intestines with the same efficiency as control mice. Collectively, these data suggest that CD8+, alpha/beta TCR+ T cells may regulate mucosal and systemic humoral immune responses to oral infection with reovirus.