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

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Abstract

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, α4β7hi memory CD8+ T cells purified from wt mice that had been orally immunized cleared RV more efficiently than α4β7low 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 α4β7hi phenotype, but subcutaneous immunization yields both α4β7hi and α4β7low 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.

Authors

Nelly A. Kuklin, Lusijah Rott, Jama Darling, James J. Campbell, Manuel Franco, Ningguo Feng, Werner Müller, Norbert Wagner, John Altman, Eugene C. Butcher, Harry B. Greenberg