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Isoform of Phosphatidylinositol 3-Kinase1Department of Laboratory Medicine and Pathology, Center for Immunology and Cancer Center, University of Minnesota, Minneapolis, MN 55455
Chemokine-mediated T cell migration is essential to an optimal immune response. The p110
isoform of PI3K is activated by G protein-coupled receptors and regulates neutrophil and macrophage chemotaxis. We used p110-deficient mice to examine the role of p110 in CD8 T cell migration and activation in response to viral challenge. Naive CD8 T cell migration in response to CCL21 in vitro and trafficking into secondary lymphoid organs in vivo was unaffected by the loss of p110. Furthermore, loss of p110 did not affect CD8 T cell proliferation and effector cell differentiation in vitro in response to anti-CD3 stimulation or in vivo in response to vaccinia virus (VV) challenge. However, there was reduced migration of p110 knockout (p110–/–) CD8 effector T cells into the peritoneum following i.p. challenge with VV. The role of p110 in CD8 effector T cell migration was intrinsic to T cells, as p110–/– CD8 effector T cells exhibited impaired migration into the inflamed peritoneum following secondary transfer into wild-type recipients. In addition, p110–/– CD8 effector T cells exhibited impaired migration in vitro in response to inflammatory chemoattractants. Although wild-type mice efficiently cleared VV at high viral doses, infection of p110 knockout mice resulted in visible illness and death less than a week after infection. Thus, p110 is dispensable for constitutive migration of naive CD8 T cells and subsequent activation and differentiation into effector CD8 T cells, but plays a central role in the migration of effector CD8 T cells into inflammatory sites.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants R01AI064271 (to Y.S.) and R37AI38903 (to S.C.J.) from the National Institutes of Health and by an American Heart Association Predoctoral Fellowship (to A.L.M.). Y.S. is supported in part by the Harry Kay Chair in Biomedical Research at the University of Minnesota.
2 Address correspondence and reprint requests to Dr. Yoji Shimizu, Department Laboratory Medicine and Pathology, Mayo Mail Code 334 Room 6-112 Nils Hasselmo Hall, University of Minnesota Medical School, 312 Church Street SE, Minneapolis, MN 55455. E-mail address: shimi002{at}umn.edu
3 Abbreviations used in this paper: CD62L, L-selectin; VV, vaccinia virus; LTB4, leukotriene B4; WT, wild type.
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