TY - JOUR
T1 - Phosphatidylinositol 3-kinase inhibitors prevent mouse cytotoxic T-cell development in vitro
AU - Phu, Tommy
AU - Mansour Haeryfar, S. M.
AU - Musgrave, Bruce L.
AU - Hoskin, David W.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0342526207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0342526207&partnerID=8YFLogxK
M3 - Article
C2 - 11358990
AN - SCOPUS:0342526207
SN - 0741-5400
VL - 69
SP - 803
EP - 814
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 5
ER -