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 gr aft infiltration and rejection, little is known regarding the effects of ra pamycin on CD8+ human T cell responses. In this study, we examined the mech anism of rapamycin-induced inhibition of Ag-driven activation of CD8(+) T c ells. 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 T CR cross-linking ex vivo. Inhibition of T cell proliferation by rapamycin w as controlled by both the strength of signal delivered through the Ag recep tor as well as the specific costimulatory signals received by the T cell. R apamycin-resistant proliferation occurred despite inhibition of p70(56) kin ase activity. Moreover, rapamycin-resistant proliferation of the CD8(+) T c ell 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 actio n of rapamycin in human disease.