α₄β₇ independent pathway for CD8⁺ T cell-mediated intestinal immunity to rotavirus

Rotavirus (RV), which replicates exclusively in cells of the small intestine, is the most important cause of severe diarrhea in young children worldwide. Using a mouse model, we show that expression of the intestinal homing integrin α₄β₇ is not essential for CD8⁺ T cells to migrate to the intestine or provide immunity to RV. Mice deficient in β7 expression (β7^-/-) and unable to express α₄β₇ integrin were found to clear RV as quickly as wild-type (wt) animals. Depletion of CD8⁺ T cells in β7^-/- animals prolonged viral shedding, and transfer of immune β7^-/- CD8⁺ T cells into chronically infected Rag-2-deficient mice resolved RV infection as efficiently as wt CD8⁺ T cells. Paradoxically, α₄β₇^hi memory CD8⁺ T cells purified from wt mice that had been orally immunized cleared RV more efficiently than α₄β₇^low CD8⁺ T cells. We explained this apparent contradiction by demonstrating that expression of α₄β₇ on effector CD8⁺ T cells depends upon the site of initial antigen exposure: oral immunization generates RV-specific CD8⁺ T cells primarily of an α₄β₇^hi phenotype, but subcutaneous immunization yields both α₄β₇^hi and α₄β₇^low immune CD8⁺ T cells with anti-RV effector capabilities. Thus, α₄β₇ facilitates normal intestinal immune trafficking to the gut, but it is not required for effective CD8⁺ T cell immunity.