A physiologic function for p-glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels

Abstract

P-glycoprotein (MDR-1) is a well-known transporter that mediates eff lux of chemotherapeutic agents from the intracellular milieu and thereby contributes to drug resistance. MDR-1 also is expressed by nonmalignant cells, including leukocytes, but physiologic functions for MDR-1 are poorly defined. Using an initial screening assay that included >100 mAbs, we observed that neutralizing mAbs MRK16, UIC2, and 4E3 against MDR-1 specifically and potently blocked basal-to-apical transendothelial migration of mononuclear phagocytes, a process that may mimic their migration into lymphatic vessels. Antagonists of MDR-1 then were used in a model of authentic lymphatic clearance. In this model, antigen-presenting dendritic cells (DC) migrate out of explants of cultured human skin and into the culture medium via dermal lymphatic vessels. DC and T cells derived from skin expressed MDR-1 on their surfaces. Addition of anti-MDR-1 mAbs MRK16, UIC2, or the MDR-1 antagonist verapamil to skin explants at the onset of culture inhibited the appearance of DC, and accompanying T cells, in the culture medium by approximately 70%. Isotype-matched control mAbs against other DC molecules including CD18, CD31, and major histocompatibility complex I did not block. In the presence of MDR-1 antagonists, epidermal DC were retained in the epidermis, in contrast to control conditions. In summary, this work identifies a physiologic function for MDR-1 during the mobilization of DC and begins to elucidate how these critical antigen-presenting cells migrate from the periphery to lymph nodes to initiate T lymphocyte-mediated immunity.

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

“…This implies that the role of P-gp is manifested early, since it is unlikely, especially in the case of the APC, that any residual Ab remained on these cells after prolonged culture. This finding is consistent with the results found by Randolph et al that preincubation of monocytes with anti-P-gp mAb inhibited reverse migration of dendritic cell precursors for up to several days (22).…”

“…In human T cells, P-gp has been reported to facilitate the cellular secretion of several cytokines, including IL-2 and IFN-␥ (19,20). In human myeloid-derived dendritic cells, MDR1 P-gp has been shown to function in transendothelial trafficking and cytokine-dependent mechanisms, possibly involving TNF-␣, (21,22). Hence, despite the provocative evidence for immunoregulatory functions of P-gp, the significance of P-gp expression for the integrity of immunological responses remains uncertain.…”

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

“…The receptors for FTY720 and FTY720-P, S1P [1][2][3][4] , when engaged by their physiological ligand S1P, have been shown to link sphingolipid signaling to chemokine receptor activity via the multidrug resistance proteins MDR1 and MRP1. Both MDR1 and MRP1 physiologically transport sphingolipid analogs, and both transporter functions are known to be essential for effective mobilization of DC from the epidermis [27][28][29]. The decreased chemotactic response of DC upon engagement of the receptors by FTY720 and FTY720-P could be considered a consequence of blocking S1P 1-4 for their physiologic ligand.…”

Migration of Langerhans cells and dermal dendritic cells in skin organ cultures: augmentation by TNF-α and IL-1 β

“…Finally, the P-glycoprotein involved in multidrug resistance (MDR-1) was shown to be an important regulator of the migration of cutaneous DCs from skin via lymph vessels. Again, this was mainly determined by antibody inhibition experiments [53].…”