Human regulatory <scp>T</scp> cells lack the cyclophosphamide‐extruding transporter <scp>ABCB</scp>1 and are more susceptible to cyclophosphamide‐induced apoptosis

Dimeloe, Sarah; Frick, Corina; Fischer, Marco; Gubser, Patrick; Razik, Leyla; Bantug, Glenn R.; Ravon, Morgane; Langenkamp, Anja; Hess, Christoph

doi:10.1002/eji.201444879

Cited by 81 publications

(53 citation statements)

References 27 publications

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“…EM CD4 + T cells had more (data not shown) and more complex (elongated/branched) mitochondria than did naive CD4 + T cells (Fig. 1A), and they demonstrated greater MitoTracker staining than did naive cells (16). Consistent with this, COXIV, a subunit of complex IV of the electron transport chain (ETC), was more abundant in EM CD4 + T cells (Fig.…”

Section: Resultssupporting

confidence: 54%

“…The study was approved by the Swiss Red Cross (blood transfusion service) and Institutional Review Board. Bulk CD4 + T cells were isolated as described previously (16) and, unless otherwise indicated, were resuspended in RPMI 1640 containing 10% AB + human serum, 50 U/ml penicillin, and 50 mg/ml streptomycin (Invitrogen, Carlsbad, CA) (RPMI/10% AB), and 50 IU/ml rIL-2 (PeproTech, Rocky Hill, NJ). Where indicated, positive selection of CD62L + cells was performed (CD62L microbeads, Miltenyi Biotech, Bergisch Gladbach, Germany) to remove CD62L + naive and central memory cells from bulk CD4 + T cells, thus enriching EM (CD62L -) cells.…”

Section: Cd4 + T Cell Isolation and Culturementioning

confidence: 99%

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The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Dimeloe

Mehling

Frick

et al. 2016

The Journal of Immunology

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Effector memory (EM) CD4+ T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4+ T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN-γ. EM CD4+ T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4+ T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (ΔΨm) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved ΔΨm and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on ΔΨm, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates ΔΨm and mitochondrial ROS production from oxygen tension changes, provides an immune-metabolic basis supporting survival, migration, and function of EM CD4+ T cells in normoxic and hypoxic conditions.

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Section: Resultssupporting

confidence: 54%

Section: Cd4 + T Cell Isolation and Culturementioning

confidence: 99%

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Dimeloe

Mehling

Frick

et al. 2016

The Journal of Immunology

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“…56 In-depth MDR1 functional analysis based on CD45RA/CCR7 expression with Mitotracker green (MTG) dye, 59 showed that naive cells (CD45RA + CCR7 + ) exclude less MTG from their cytoplasm than CD4 + effector (CD45RA neg CCR7 neg , T EM ) and central (CD45RA neg CCR7 +, T CM ) memory cells. 60 The majority of CD4 + T cells expressing MDR1 are therefore memory cells with the exception of Treg (FoxP3 + or CD25 high CD127 low/neg ) lacking MDR1 expression. 60 However, their described hyper-sensitivity to cyclophosphamide does not rely on that since this drug is not a MDR1 substrate.…”

Section: Introductionmentioning

confidence: 99%

“…60 The majority of CD4 + T cells expressing MDR1 are therefore memory cells with the exception of Treg (FoxP3 + or CD25 high CD127 low/neg ) lacking MDR1 expression. 60 However, their described hyper-sensitivity to cyclophosphamide does not rely on that since this drug is not a MDR1 substrate.…”

Section: Introductionmentioning

confidence: 99%

MDR1 in immunity: friend or foe?

et al. 2018

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MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options.

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“…Paclitaxel also reduced the number of regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and led to the augmentation of the functions of CD4 and CD8 T cells (16,17). In other cases, DNA alkylating agents, such as cyclophosphamide and mafosfamide, in low doses selectively depleted Treg cells (18,19), caused an increase in effector T cells (Teff)/Treg cell ratios via up-regulation of the T helper (Th) 17 pathway (20), and improved the outcome of tumor vaccinations against cancer (21)(22)(23). Furthermore, doxorubicin, mitomycin C, vinblastine, and methotrexate in low doses have been found to up-regulate DC maturation, antigen processing, and antigen presentation, which led to synergistic antitumor effects of low-dose chemotherapy combined with a DC vaccine (24)(25)(26).…”

Section: Significancementioning

confidence: 99%

In vivo amelioration of endogenous antitumor autoantibodies via low-dose P₄N through the LTA4H/activin A/BAFF pathway

Lin

Tsai

Hsieh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cancer progression is associated with the development of antitumor autoantibodies in patients' sera. Although passive treatment with antitumor antibodies has exhibited remarkable therapeutic efficacy, inhibitory effects on tumor progression by endogenous antitumor autoantibodies (EAAs) have been limited. In this study, we show that P 4 N, a derivative of the plant lignan nordihydroguaiaretic acid (NDGA), enhanced the production of EAAs and inhibited tumor growth at low noncytotoxic concentrations via its immunoregulatory activity. Intratumoral injection of P 4 N improved the quantity and quality of EAAs, and passive transfer of P 4 N-induced EAAs dramatically suppressed lung metastasis formation and prolonged the survival of mice inoculated with metastatic CT26 tumor cells. P 4 N-induced EAAs specifically recognized two surface antigens, 78-kDa glucose-regulated protein (GRP78) and F1F0 ATP synthase, on the plasma membrane of cancer cells. Additionally, P 4 N treatment led to B-cell proliferation, differentiation to plasma cells, and high titers of autoantibody production. By serial induction of autocrine and paracrine signals in monocytes, P 4 N increased B-cell proliferation and antibody production via the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway. This mechanism provides a useful platform for studying and seeking a novel immunomodulator that can be applied in targeting therapy by improving the quantity and quality of the EAAs.endogenous antitumor autoantibody | P 4 N | B-cell proliferation | colorectal cancer | cancer immunotherapy

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Human regulatory T cells lack the cyclophosphamide‐extruding transporter ABCB1 and are more susceptible to cyclophosphamide‐induced apoptosis

Abstract: ATP-binding cassette (ABC) transporters, including ABC-transporter B1 (ABCB1),

Cited by 81 publications

References 27 publications

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

MDR1 in immunity: friend or foe?

In vivo amelioration of endogenous antitumor autoantibodies via low-dose P₄N through the LTA4H/activin A/BAFF pathway

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Human regulatory T cells lack the cyclophosphamide‐extruding transporter ABCB1 and are more susceptible to cyclophosphamide‐induced apoptosis

Abstract: ATP-binding cassette (ABC) transporters, including ABC-transporter B1 (ABCB1),

Cited by 81 publications

References 27 publications

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

MDR1 in immunity: friend or foe?

In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway

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Product

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In vivo amelioration of endogenous antitumor autoantibodies via low-dose P₄N through the LTA4H/activin A/BAFF pathway