Rapamycin-resistant proliferation of CD8+ T cells correlates with p27kip1 down-regulation and bcl-xL induction, and is prevented by an inhibitor of phosphoinositide 3-kinase activity.
Rapamycin inhibits the proliferation of many mammalian cell types, including lymphocytes, making the compound useful as an immunosuppressant. Rapamycin has also been a useful tool for studying signaling mechanisms regulating cellular proliferation. However, the effects of rapamycin remain poorly understood, and the precise mechanisms of clinical action remain elusive. Previously, we found that, depending on the strength of the signal delivered to the T cell via both the T cell receptor and the costimulatory molecule CD28, CD8+ T cells are capable of rapamycin-resistant proliferation. Here, we have further elucidated the mechanism of rapamycin-resistant proliferation of human CD8+ T cells. Under conditions where rapamycin inhibited proliferation, p27kip1 down-regulation was prevented, whereas under conditions resulting in rapamycin-resistant proliferation, p27kip1 was down-regulated. Further, T cell receptor/CD28-dependent induction of bcl-xL expression was not inhibited by rapamycin, which correlated with both rapamycin-resistant proliferation and increased cell survival. Moreover, an inhibitor of phosphoinositide 3-kinase activity was able to eliminate rapamycin-resistant proliferation of freshly isolated CD8+ human cells, strongly suggesting that phosphoinositide 3-kinase activity was required for the rapamycin-resistant proliferation of CD8+ T cells. The selective immunosuppressive effect of rapamycin in human CD8+ T cell populations could be predictive of a selective effect allowing cytotoxic responses during microbial infections where there are strong strengths of signals associated with high affinity T cell receptors and strong costimulatory second signals. In contrast, the weaker autoimmune and perhaps allogeneic responses can be selectively inhibited by the actions of rapamycin.
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. jslavik@rics.bwh.harvard.edu
Jacqueline M
JM
Slavik
Dong-Gyun
DG
Lim
Steven J
SJ
Burakoff
David A
DA
Hafler
D017304:Annexin A5 / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002455:Cell Division; D004396:Coloring Agents / Q000494:pharmacology; D056741:Cyclin D; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004952:Esters / Q000737:chemistry; D005452:Fluoresceins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D051020:bcl-X Protein
D017304:Annexin A5; D000903:Antibiotics, Antineoplastic; C494811:BCL2L1 protein, human; D018106:CD28 Antigens; D017252:CD3 Complex; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D056741:Cyclin D; D016213:Cyclins; D004791:Enzyme Inhibitors; D004952:Esters; D005452:Fluoresceins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; C027780:carboxyfluoresceindiacetate; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases; D020123:Sirolimus