MDR1 P-glycoprotein (P-gp), the multidrug resistance-associated transmembra
ne transporter, is physiologically expressed by human peripheral immune cel
ls, but its role in cell-mediated immunity remains poorly understood. Here,
we demonstrate a novel role for P-gp in alloantigen-dependent human T cell
activation. The pharmacologic P-gp inhibitor tamoxifen (1-10 muM) and the
MDR1 P-gp-specific mAb Hyb-241 (1-20 mug/ml), which detected surface P-gp o
n 21% of human CD3(+) T cells and 84% of CD14(+) APCs in our studies, inhib
ited alloantigen-dependent, but not mitogen-dependent, T cell proliferation
in a dose-dependent manner from 40-90% (p < 0.01). The specific inhibitory
effect on alloimmune T cell activation was associated with > 85% inhibitio
n (p < 0.01) of IL-2, IFN-gamma, and TNF-alpha production in 48-h MLR cocul
ture supernatants. Addition of recombinant human IL-2 (0.1-10 ng/ml) restor
ed proliferation in tamoxifen-treated cocultures. Pretreatment of purified
CD4(+) T cells with Hyb-241 mAb before coculture resulted in inhibition of
CD4+ T cellular IFN-gamma secretion. Also, blockade of P-gp on allogeneic A
PCs inhibited IL-12 secretion. Taken together these results demonstrate tha
t P-gp is functional on both CD4+ T cells and CD14+ APCs, and that P-gp blo
ckade may attenuate both IFN-gamma and IL-12 through a positive feedback lo
op, Our results define a novel role for P-gp in alloimmunity and thus raise
the intriguing possibility that P-gp may represent a novel therapeutic tar
get in allograft rejection. The Journal of Immunology, 2001, 166: 2451-2459
.