Journal of Leukocyte Biology
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(Journal of Leukocyte Biology. 2001;69:803-814.)
© 2001 by Society for Leukocyte Biology

Phosphatidylinositol 3-kinase inhibitors prevent mouse cytotoxic T-cell development in vitro

Tommy Phu, S. M. Mansour Haeryfar, Bruce L. Musgrave and David W. Hoskin

Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada

Correspondence: David W. Hoskin, Department of Microbiology and Immunology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada. E-mail: dwhoskin{at}is.dal.ca

To become competent killer cells, CD8+ T cells require stimulation through signal transduction pathways associated with the T-cell receptor, costimulatory molecules such as CD28, and cytokine receptors such as the interleukin (IL)-2 receptor. We used wortmannin and LY294002, two inhibitors of phosphatidylinositol 3-kinase (PI3-K), to study the role of PI3-K in mouse cytotoxic T-lymphocyte (CTL) induction in response to mitogenic anti-CD3 antibody. Anti-CD3-induced CD8+ T-cell proliferation and CTL development were inhibited dose dependently by both PI3-K inhibitors. IL-2 synthesis by anti-CD3-activated CD8+ T cells was also diminished by PI3-K inhibition. PI3-K inhibition resulted in a modest decrease in anti-CD3-induced CD4+ T-cell proliferation but failed to affect IL-2 expression by anti-CD3-activated CD4+ T cells. PI3-K inhibition during CTL induction resulted in decreased levels of mRNAs coding for granzyme B, perforin, and Fas ligand. In addition, CTL induced in the presence of PI3-K inhibitors failed to conjugate normally with P815 target cells. Exogenous IL-2 did not reverse the effects of PI3-K inhibition on CD8+ T-cell proliferation and CTL induction. These results support the conclusion that PI3-K activation is involved in T-cell receptor, CD28, and IL-2 receptor signaling of CD8+ T cells. PI3-K is, therefore, an important component of multiple signal transduction pathways involved in CTL generation.

Key Words: phosphoinositide 3-kinase • cytotoxic T lymphocyte • signal transduction • proliferation • gene expression • adhesion molecules • cytotoxic effector function






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