Differential activity of P‐glycoprotein in normal blood lymphocyte subsets

Abstract

Summary.To better understand the phenomenon of Pglycoprotein (P-170) expression we investigated lymphocyte subpopulations for P-170 function in healthy volunteers. Studies were based on three-colour flow cytometry including the fluorescent probe rhodamine 123 (Rh123), which is transported by P-170. Marked Rh123 efflux was detected in CD8 þ T lymphocytes with CD8 þ /CD45RA þ T cells (naive cells) showing significantly higher P-170 activity as compared with CD8 cells (memory cells) demonstrated less P-170 activity than CD8þ /CD45RO ¹ cells (P < 0·04). P-170 function was less prominent in CD4 þ T cells, however, Rh123 efflux was higher in the CD4 þ /CD45RA þ and CD4 þ / CD45RO ¹ subpopulations (P < 0·025) corresponding to the CD8 þ results. Dye efflux differed significantly between activated and non-activated CD8 þ and CD4 þ as well as CD8 þ /CD11b þ and CD8 þ /CD11b ¹ T lymphocytes. Since CD16 þ natural killer cells (NK) expressed the highest level of P-170, the NK cytotoxicity against 51 Cr-labelled K562 target cells was assayed in the presence or absence of P-170 inhibitors. NK related cytotoxicity was significantly reduced in the presence of R-verapamil and dexnigaldipine-HCP in a dose-dependent manner.The differential expression of P-170 activity in naive and memory T cells together with the reduced NK related cytotoxicity in the presence of MDR-modulators suggest a physiological role of P-170 in immunological functions of these lymphocyte subsets. Consequently, the addition of MDR modulators to conventional chemotherapy as a strategy to overcome drug resistance should consider possible adverse immunosuppressive effects.

P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy

“…Inhibition of P-gp resulted in a decreased cytotoxicity of NK cells (21, 152). The decrease in the lytic activities of NK cells in the presence of R-verapamil, an inhibitor of P-gp, was dose dependent (89). However, no difference in cytotoxic T-cell function was found between wild-type mice and P-gp-knockout mice (39).…”

MDR1 in immunity: friend or foe?

“…52 Inhibition with verapamil decreases their cytotoxic functions in a dose dependent manner. 53 MDR1 might indeed influence the intracellular pH in NK cells and thereby their cytotoxic function. 54 Using cardiac drugs (AHC-93 and nicardipine) that are also MDR1 inhibitors, Takahashi et al .…”

P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells

“…62,63 Natural killer (NK) cells also express high levels of Pgp and should be protected from PDCT toxic effects. 28,64 Although we demonstrate here that PDCT is effective at eliminating T cells reactive to stimulator cell MHC antigens, the effect of PDCT on minor histocompatibility antigen (MiHA)-stimulated T cells has yet to be addressed. 36,65 In addition, the observation that TH9402-treated T cells respond to third-party MHC antigens indicates preservation of T-cell signaling and effector pathways that should translate into elimination of viral and fungal invaders.…”

“…26 Pgp, the product of the multidrug-resistance-1 (MDR1) gene, is a protein expressed not only in normal stem cells, but also in T lymphocytes. [27][28][29][30] Investigators have proposed that T-cell activation may actually lead to the inactivation of Pgp. 29 Thus, activated T cells should fail to extrude rhodamine.…”