Our recent work has demonstrated that the immunosuppressive drug rapamycin selectively affects the CsA-resistant pathway. Our initial studies have focused on the mechanism of activation of the IL-2 gene in a CsA-resistant manner. We found that the effect of rapamycin on the IL-2 expression was due to alteration in IL-2 mRNA stability. More recently, we have also shown that activation of T cells by IL-12 is resistant to CsA, but sensitive to rapamycin. As the intracellular target of rapamycin is mTOR (mammalian target of rapamycin), we are investigating the mechanism of activation of mTOR during T cell activation. Regarding the physiological role of the resistant pathway, we have observed the effect of cytokine signaling, particularly the combination of IL-12 and IL-18 but not individual cytokine alone, in activating resting human peripheral blood T cells in producing IFN-in a CsA-resistant, but rapamycin-sensitive manner. Interestingly, nave CD4+ T cells are more responsive to IL-12 plus IL-18 stimulation in comparison to memory CD4+ T cells. This cytokine-mediated activation of resting T cells is independent of antigen. We are currently investigating the in vivo physiological role of this cytokine signaling pathway.
| Kusaba, Hitoshi; Ghosh, Paritosh; Derin, Rachel et al. (2005) Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR). J Biol Chem 280:1037-43 |
| Ghosh, Paritosh; Buchholz, Meredith A; Yano, Shingo et al. (2002) Effect of rapamycin on the cyclosporin A-resistant CD28-mediated costimulatory pathway. Blood 99:4517-24 |
