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RNA-Seq of Day 6 in vitro generated cells with and without Mdr1 expression and Elacridar treatment

ABSTRACT: Multidrug resistance (MDR)-1 acts as a chemotherapeutic drug efflux pump in tumor cells, although its physiologic functions remain enigmatic. Using a recently-developed MDR1-knockin reporter allele (Abcb1aAME/+), we found that constitutive MDR1 expression amongst hematopoietic cells was observed mainly in cytolytic lymphocytes—including CD8+ cytotoxic T lymphocytes (CTL) and natural killer cells—and regulated by Runt-related (Runx) transcription factors. Although MDR1 was dispensable for naïve CD8+ T cell development, it was required for both normal accumulation of effector CTL following acute viral infection and protective function of memory CTL upon challenge with an intracellular bacterium. MDR1 acted early after naïve CD8+ T cell activation to suppress oxidative stress, enforce survival and safeguard mitochondrial function in developing CTL. Together, these data highlight an important endogenous function of MDR1 in cell-mediated immune responses, and suggest that ongoing efforts to intentionally inhibit MDR1 in cancer patients could be counter-productive.

ORGANISM(S): Mus musculus

PROVIDER: GSE143139 | GEO | 2020/02/28

REPOSITORIES: GEO

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scRNA-seq analyses on Thy1.1+Thy1.2+ MDR1-sufficient and Thy1.1+Thy1.2- MDR1-deficient P14 CD8+ T cells from ten congenically-transferred and LCMV-infected wild type B6 mice at day 8 post-infection

Project description:Multidrug resistance (MDR)-1 acts as a chemotherapeutic drug efflux pump in tumor cells, although its physiologic functions remain enigmatic. Using a recently-developed MDR1-knockin reporter allele (Abcb1aAME/+), we found that constitutive MDR1 expression amongst hematopoietic cells was observed mainly in cytolytic lymphocytes—including CD8+ cytotoxic T lymphocytes (CTL) and natural killer cells—and regulated by Runt-related (Runx) transcription factors. Although MDR1 was dispensable for naïve CD8+ T cell development, it was required for both normal accumulation of effector CTL following acute viral infection and protective function of memory CTL upon challenge with an intracellular bacterium. MDR1 acted early after naïve CD8+ T cell activation to suppress oxidative stress, enforce survival and safeguard mitochondrial function in developing CTL. Together, these data highlight an important endogenous function of MDR1 in cell-mediated immune responses, and suggest that ongoing efforts to intentionally inhibit MDR1 in cancer patients could be counter-productive.

2020-02-28 | GSE143140 | GEO

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Project description:The aim of this study was to characterize the transcriptional signature of MDR1+ human memory T cells isolated from clinically inflamed gut tissue, and compare it to local MDR1- memory T cells Human mononuclear cells were isolated from the peripheral blood of a healthy adult donor (Ficol density centrifugation) or from resected lesioned gut tissue of a patient with active Crohn's disease. For cell isolation from gut tissue, tissue was rinsed with PBS, treated with 0.15% DTT to remove mucous, then with 1 mM EDTA to remove epithelial cells and intra-epithelial lymphocytes. Remaining tissue was digested using Liberase-TL (Roche) plus 10 U/mL DNase I. Mononuclear cells were then filtered through 70 mM nylon filters and isolated via a 30%/ 70% Percol gradient. Mononuclear cells from blood or gut tissue were FACS-sorted into CD3+ CD4+ CD45RO+ MDR1+ or MDR1- memory T cells, using Rhodamine 123 (Rh123) efflux as a surrogate for MDR1 expression/ activity. Sorted cells were harvested directly ex vivo (without further in vitro culture or manipulation) prior to RNA extraction. MDR1- memory CD4+ T cells vs. MDR1+ memory CD4+ T cells from healthy donor peripheral blood or from active Crohn's disease lesioned tissue; MDR1- or MDR1+ memory CD4+ T cells from blood vs. inflamed gut tissue

2013-12-17 | E-GEOD-49702 | biostudies-arrayexpress

Physiologic expression and function of the MDR1 transporter in cytotoxic T lymphocytes

Project description:Physiologic expression and function of the MDR1 transporter in cytotoxic T lymphocytes

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Expression profiling of MDR1+ and MDR1- human memory T cells from the blood and clinically-inflamed gut tissue

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The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids

Project description:This SuperSeries is composed of the SubSeries listed below. CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn?s disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn?s disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.

2020-01-10 | GSE143405 | GEO

The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids [Rh123hi-lo RNA-Seq]

Project description:CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn’s disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn’s disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.

2020-01-10 | GSE143404 | GEO

The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids [shMdr1 RNA-seq in vivo]

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MDR1 Drug Efflux Pump Promotes Acquired and Intrinsic Resistance to Protein Degraders in Cancer Cells

Project description:PROTACs (Proteolysis-Targeting Chimeras) represent a revolutionary new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to protein degraders remains poorly understood. Here, we applied proteomics approaches to elucidate resistance mechanisms to protein degrader therapies in cancer cells. Our studies revealed acquired resistance to degrader therapies in cancer cells can be mediated by upregulation of the ATP-dependent drug efflux pump MDR1. Degrader-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, MDR1 is frequently overexpressed in cancer, and cancer cell lines overexpressing MDR1 exhibited intrinsic resistance to protein degraders, requiring co-treatment with MDR1 inhibitors to achieve protein degradation and therapeutic response. Notably, co-treatment of MDR1-overexpressing K-ras mutant colorectal cancer cells with MEK1/2 or K-ras degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 activity and ErbB receptor-driven resistance. Together, our findings showed overexpression of MDR1 can promote both intrinsic and acquired resistance to protein degraders in cancer cells and that concurrent blockade of MDR1 will likely be required to achieve durable protein degradation and therapeutic response.

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