Uncoupling p70(s6) kinase activation and proliferation: rapamycin-resistant proliferation of human CD8(+) T lymphocytes.
Rapamycin is a fungal macrolide that inhibits the proliferation of T cells. Studies in both animals and humans have found that rapamycin significantly reduces graft rejection. However, though CD8(+) T cells are involved in graft infiltration and rejection, little is known regarding the effects of rapamycin on CD8(+) human T cell responses. In this study, we examined the mechanism of rapamycin-induced inhibition of Ag-driven activation of CD8(+) T cells. Surprisingly, a heterogeneous proliferative response in the presence of rapamycin was observed among different Ag-specific CD8(+) T cell clones; this was also observed in CD8(+) peripheral blood T cells activated with TCR cross-linking ex vivo. Inhibition of T cell proliferation by rapamycin was controlled by both the strength of signal delivered through the Ag receptor as well as the specific costimulatory signals received by the T cell. Rapamycin-resistant proliferation occurred despite inhibition of p70(s6) kinase activity. Moreover, rapamycin-resistant proliferation of the CD8(+) T cell clones was blocked by anti-IL-2 Abs, suggesting that while some of the parallel pathways triggered by IL-2R signaling are sensitive to the effects of rapamycin, others account for the Ag-driven rapamycin resistance. These data provide a new framework for examining the specific mechanism of action of rapamycin in human disease.
Slavik
J M
JM
Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Lim
D G
DG
Burakoff
S J
SJ
Hafler
D A
DA
D000911:Antibodies, Monoclonal / Q000378:metabolism; D018801:CD2 Antigens / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D002461:Cell Line, Transformed; D002999:Clone Cells; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015234:HLA-A Antigens / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008285:Major Histocompatibility Complex / Q000276:immunology; D018448:Models, Immunological; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus