α4β7 independent pathway for CD8+ T cell–mediated intestinal immunity to rotavirus
Nelly A. Kuklin, … , Eugene C. Butcher, Harry B. Greenberg
Nelly A. Kuklin, … , Eugene C. Butcher, Harry B. Greenberg
Published December 15, 2000
Citation Information: J Clin Invest. 2000;106(12):1541-1552. https://doi.org/10.1172/JCI10927.
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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.