Journal
JOURNAL OF IMMUNOLOGY
Volume 166, Issue 4, Pages 2451-2459Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.166.4.2451
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- NIAID NIH HHS [AI33100, AI46756] Funding Source: Medline
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MDR1 P-glycoprotein (P-gp), the multidrug resistance-associated transmembrane transporter, is physiologically expressed by human peripheral immune cells, 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 on 21% of human CD3(+) T cells and 84% of CD14(+) APCs in our studies, inhibited 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% inhibition (p < 0.01) of IL-2, IFN-gamma, and TNF-alpha production in 48-h MLR coculture supernatants. Addition of recombinant human IL-2 (0.1-10 ng/ml) restored 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 APCs inhibited IL-12 secretion. Taken together these results demonstrate that P-gp is functional on both CD4+ T cells and CD14+ APCs, and that P-gp blockade may attenuate both IFN-gamma and IL-12 through a positive feedback loop, 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 target in allograft rejection. The Journal of Immunology, 2001, 166: 2451-2459.
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