A multidrug-resistance protein (MRP)-like transmembrane pump is highly expressed by resting murine T helper (Th) 2, but not Th1 cells, and is induced to equal expression levels in Th1 and Th2 cells after antigenic stimulation in vivo.

Lohoff, Michael; Prechtl, Stefan; Sommer, Frank; Roellinghoff, M; Schmitt, Earlene M.; Gradehandt, Gernot; Rohwer, P.; Stride, Brenda D.; Cole, Susan P.C.; Deeley, Roger G.

doi:10.1172/jci824

Cited by 39 publications

(30 citation statements)

References 39 publications

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“…Thereafter, the clones were processed for fluorescence staining of an intracellular mrp1 epitope with mAb MRPr1. Resting Th1 cells displayed a weak mrp1 signal compared with resting Th2 cells, confirming our earlier observations (15). After cytokine stimulation, mrp1 expression was unchanged in Th2 cells, but was elevated in Th1 cells to almost the same level as in Th2 cells.…”

Section: Detection Of Mrp1 In Cd4supporting

confidence: 91%

“…The results are representative of six independent experiments. obtained when the Th1 cells were cocultured with PSC 833, a different MRP inhibitor (15), instead of MK571 (data not shown). In addition, the effect of MK571 was not restricted to Th1 cells in that the Ag-induced secretion of IL-4 by Th2 cells was also distinctly blocked by simultaneous incubation with MK571 (Fig.…”

Section: The Specific Mrp Inhibitor Mk571 Suppresses Th Cell Activationmentioning

confidence: 98%

“…The highest preference for Th2 lymphocytes was shown by the chemokine receptor CCR4 (11,13). Recently, we have described (15) another candidate for Th1 and Th2 discrimination, namely, a transmembrane transporter molecule. The protein exports the fluorescent anion Fluo-3 out of the cytoplasm of T cells (16) and is differentially expressed in resting Th1 and Th2 cells: resting Th2 cells transport Fluo-3 whereas Th1 cells are unable to do so.…”

Section: Urine Cd4mentioning

confidence: 99%

“…Dye extrusion inhibition studies raised the possibility that the Fluo-3 anion pump was mrp1 (15). In experiments described here, we attempted to formally prove that mrp1 transports the Fluo-3 anion using HEK 293 cells transfected with the episomal expression vector pcEBV7 containing either the human MRP1 or the murine mrp1 cDNA (28).…”

Section: Transfection Of Mrp1 Cdna Enables Formerly Inactive Cells Tomentioning

confidence: 99%

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The Multidrug Resistance Protein 1: A Functionally Important Activation Marker for Murine Th1 Cells

Prechtl¹,

Roellinghoff²,

Scheper

et al. 2000

The Journal of Immunology

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Previously, we described the expression of an energy-dependent pump in resting murine Th2 (but not resting Th1) cells which extruded the fluorescent dye Fluo-3. After stimulation with Ag and APCs, Th1 cells also expressed this pump. Furthermore, expression of the murine multidrug resistance protein 1 (mrp1) correlated with the presence of the pump. In this study, we report that Fluo-3 is indeed transported by murine mrp1 or its human ortholog MRP1, as revealed by transfection of HEK 293 cells with mrp1 or MRP1 cDNA. Like antigenic activation, IL-2 dose-dependently enhanced the Fluo-3-extruding activity in murine Th1 cells. Although TNF-α and IL-12 by themselves only weakly enhanced Fluo-3 extrusion, each of them did so in strong synergism with IL-2. An Ab directed against mrp1 was used to quantify the expression of mrp1 protein in T cells at the single-cell level. Like the Fluo-3 pump, mrp1 protein expression was enhanced by IL-2. Immunohistochemical studies using confocal laser microscopy indicated that mrp1 is localized mainly at the plasma membrane. In addition, protein expression of mrp1 was induced in Vβ8+CD4+ T cells 12 h after in vivo application of Staphylococcal enterotoxin B. Finally, mrp1 was functionally relevant during the activation process of Th1 cells, because T cell activation could be suppressed by exposure of cells to the mrp1 inhibitor MK571. Thus, we present mrp1 as a novel, functionally important activation marker for Th1 cells and short-term in vivo activated CD4+ T cells, whereas its expression seems to be constitutive in Th2 cells.

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Section: Detection Of Mrp1 In Cd4supporting

confidence: 91%

Section: The Specific Mrp Inhibitor Mk571 Suppresses Th Cell Activationmentioning

confidence: 98%

Section: Urine Cd4mentioning

confidence: 99%

Section: Transfection Of Mrp1 Cdna Enables Formerly Inactive Cells Tomentioning

confidence: 99%

See 2 more Smart Citations

The Multidrug Resistance Protein 1: A Functionally Important Activation Marker for Murine Th1 Cells

Prechtl¹,

Roellinghoff²,

Scheper

et al. 2000

The Journal of Immunology

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“…We assessed their functional activity by loading purified T cells with a fluorescent transport substrate in the presence of various doses of FTY720, and measuring the units of fluorescence retained in the cells over a period of time (23). Loss of fluorescence at 37°C indicates transport of the dye from the intracellular to the extracellular compartment, while cells held at 4°C do not export dye (7,24). The substrate Fluo-3 requires Abcc1 for transport (13), while the substrate DiOC 2 is transported by Abcb1 more efficiently than by Abcc1 (G.J.…”

Section: Fty720 Stimulates Multidrug Transporter Efflux Activitymentioning

confidence: 99%

FTY720 stimulates multidrug transporter– and cysteinyl leukotriene–dependent T cell chemotaxis to lymph nodes

Honig¹,

Fu²,

Mao³

et al. 2003

J. Clin. Invest.

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IntroductionFTY720 is a synthetic sphingosine immunosuppressant that prolongs the survival of allografts without impairing normal T and B cell activation (1). In vitro studies have proposed that FTY720, like other sphingosine derivatives, may cause apoptotic death of the T cell, although the concentrations needed for this effect are greater than the normal therapeutic dose (2). FTY720 may also prolong graft survival by decreasing T cell infiltration into allografts or otherwise altering normal T cell trafficking. Recent studies demonstrate the disappearance of lymphocytes, especially T cells, from peripheral blood and spleen within 3-24 hours after a single oral dose of the drug. Concurrently, there is a marked increase in the number of lymphocytes in peripheral LNs, mesenteric LNs, and Peyer's patches (3). The LN sequestration of lymphocytes may be involved in the immunosuppressive effects of FTY720, as regulated trafficking of lymphocytes is necessary for systemic immune responses and allograft rejection (4, 5).A recent report demonstrates that FTY720 becomes phosphorylated in vivo and then acts as a potent agonist for multiple sphingosine-1-phosphate (S1P) receptors (S1PRs) (6). S1PR activation seems responsible for downstream events that lead to lymphocyte homing. However, the cellular and molecular mechanisms are not understood. Recent studies demonstrate a novel role for lipid mediators in LN homing of DCs. A blind screening of neutralizing mAb's led to the discovery that the lipid transporter ABCB1 (previously called MDR-1 and P-glycoprotein; for new nomenclature, see http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html) regulates human DC migration to afferent lymphatics (7). Coupled with the hydrolysis of ATP, ABCB1 transports a wide range of compounds with various structures and targets, including ceramide analogs (8) and platelet-activating factor (9, 10), from the cytosol to the extracellular environment. A subsequent study demonstrated a role for another lipid transporter, Abcc1 (previously called Mrp1), in the migration of DCs to lymphatics. Abcc1 physiologically transports sphingolipid analogs and cysteinyl leukotriene C 4 (LTC 4 ), which is metabolized in the extracellular environment to LTD 4 and LTE 4 (11, 12). Mice lacking the Abcc1 gene show markedly decreased migration of Langerhans cells to LNs. Administration of exogenous cysteinyl leukotrienes (cysLTs) restores DC migration in these mice (13). These studies also demonstrate that both transporters are required for human DC migratory activity. However, whether the two transporters function in an interactive manner remains unclear (13,14).The mechanism by which Abcc1 causes LN homing of DCs was further shown to be chemokine-mediated. FTY720 is a sphingosine-derived immunosuppressant. Phosphorylated FTY720 promotes T cell homing from spleen and peripheral blood to LNs by acting as an agonist for sphingosine-1-phosphate (S1P) receptors. Here we demonstrate that FTY720 enhances the activity of the sphingosine transporter Abcb1 (Mdr1) and ...

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Th1/Th2 cells

2007

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A large body of evidence indicates the existence of functionally polarized CD4+ T‐cell responses based on their profile of cytokine secretion. Type 1 T helper (Th1) cells produce interferon‐gamma, interleukin (IL)‐2, and tumor necrosis factor (TNF)‐β, which activate macrophages and are responsible for cell‐mediated immunity and phagocyte‐dependent protective responses. By contrast, type 2 Th (Th2) cells produce IL‐4, IL‐5, IL‐10, and IL‐13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions, thus providing phagocyte‐independent protective responses. Th1 cells mainly develop following infections by intracellular bacteria and some viruses, whereas Th2 cells predominate in response to infestations by gastrointestinal nematodes. Polarized Th1 and Th2 cells not only exhibit different functional properties, but also show the preferential expression of some activation markers and distinct transcription factors. Several mechanisms may influence the Th cell differentiation, which include the cytokine profile of “natural immunity” evoked by different offending agents, the nature of the peptide ligand, as well as the activity of some costimulatory molecules and microenvironmentally secreted hormones, in the context of the individual genetic background. In addition to playing different roles in protection, polarized Th1‐type and Th2‐type responses are also responsible for different types of immunopathological reactions. Th1 cells are involved in the pathogenesis of organ‐specific autoimmune disorders, Crohn's disease, Helicobacter pylori‐induced peptic ulcer, acute kidney allograft rejection, and unexplained recurrent abortions. In contrast, allergen‐specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals. Moreover, Th2 responses against still unknown antigens predominate in Omenn's syndrome, idiopathic pulmonary fibrosis, and progressive systemic sclerosis. Finally, the prevalence of Th2 responses may play some role in a more rapid evolution of human immunodeficiency virus infection to the full‐blown disease. The Th1/Th2 paradigm also provides the rationale for the development of new types of vaccines against infectious agents and of novel strategies for the therapy of allergic and autoimmune disorders.

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A multidrug-resistance protein (MRP)-like transmembrane pump is highly expressed by resting murine T helper (Th) 2, but not Th1 cells, and is induced to equal expression levels in Th1 and Th2 cells after antigenic stimulation in vivo.

Cited by 39 publications

References 39 publications

The Multidrug Resistance Protein 1: A Functionally Important Activation Marker for Murine Th1 Cells

The Multidrug Resistance Protein 1: A Functionally Important Activation Marker for Murine Th1 Cells

FTY720 stimulates multidrug transporter– and cysteinyl leukotriene–dependent T cell chemotaxis to lymph nodes

Th1/Th2 cells

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