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

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

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

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Wt mice (C57BL/6) were immunized twice at a 15-day interval either subcu...
Wt mice (C57BL/6) were immunized twice at a 15-day interval either subcutaneously or orally with RV as described. Thirty days following the last immunization, the memory CD8+ T cells from the spleen were separated by FACS into α4β7hi or α4β7low fractions and subsequently injected into chronically infected Rag-2 mice. The data represent one of two experiments performed with similar results. (a) Stool Ag shedding of RV-infected Rag-2 mice adoptively transferred with 30,000 α4β7low memory CD8+ T cells purified from mice orally immunized with live RV. (b) Virus shedding of RV-infected Rag-2 mice adoptively transferred with 30,000 α4β7low memory CD8+ T cells purified from mice systemically immunized with inactivated RV. (c) Stool Ag shedding of RV-infected Rag-2 mice adoptively transferred with 10,000 α4β7hi memory CD8+ T cells purified from mice orally immunized with live RV. (d) Stool Ag shedding of RV-infected Rag-2 mice adoptively transferred with 10,000 α4β7hi memory CD8+ T cells purified from mice systemically immunized with inactivated RV. Circles indicate RV shedding of Rag-2 mice transferred with CD8+ T cells from orally immunized donors. Squares indicate RV shedding of Rag-2 mice transferred with CD8+ T cells from systemically primed donors. Filled symbols indicate Ag shedding of Rag-2 mice adoptively transferred with α4β7hi CD8+ T cells. Open symbols indicate Ag shedding of Rag-2 mice adoptively transferred with α4β7low CD8+ T cells.