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Chronic Methadone Use Alters the CD8+ T Cell Phenotype In Vivo and Modulates Its Responsiveness Ex Vivo to Opioid Receptor and TCR Stimuli

Claire Mazahery, Bryan L. Benson, Angélica Cruz-Lebrón and Alan D. Levine
J Immunol January 22, 2020, ji1900862; DOI: https://doi.org/10.4049/jimmunol.1900862
Claire Mazahery
*Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
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Bryan L. Benson
*Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
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Angélica Cruz-Lebrón
†Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106;
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Alan D. Levine
*Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
†Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106;
‡Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106;
§Department of Medicine, Case Western Reserve University, Cleveland, OH 44106;
¶Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106; and
‖Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106
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Key Points

  • Methadone use alters circulating CD8+ T cell subsets, decreasing TEMRA cell frequency.

  • Expression of the opioid receptors and TCRs is not modulated by methadone use.

  • Ex vivo stimulation of μ-OR or δ-OR produces distinct surface marker patterns.

Abstract

Endogenous opioid peptides are released at sites of injury, and their cognate G protein–coupled opioid receptors (ORs) are expressed on immune cells. Although drugs of misuse appropriate ORs, conflicting reports indicate immunostimulatory and immunosuppressive activity, in that opioid users have elevated infection risk, opioids activate innate immune cells, and opioids attenuate inflammation in murine T cell–mediated autoimmunity models. The i.v. use of drugs transmits bloodborne pathogens, particularly viruses, making the study of CD8+ T cells timely. From a cohort of nonuser controls and methadone users, we demonstrate, via t-Stochastic Neighbor Embedding and k-means cluster analysis of surface marker expression, that chronic opioid use alters human CD8+ T cell subset balance, with notable decreases in T effector memory RA+ cells. Studying global CD8+ T cell populations, there were no differences in expression of OR and several markers of functionality, demonstrating the need for finer analysis. Purified CD8+ T cells from controls respond to opioids ex vivo by increasing cytoplasmic calcium, a novel finding for OR signal transduction, likely because of cell lineage. CD8+ T cells from controls exposed to μ-OR agonists ex vivo decrease expression of activation markers CD69 and CD25, although the same markers are elevated in μ-OR–treated cells from methadone users. In contrast to control cells, T cell subsets from methadone users show decreased expression of CD69 and CD25 in response to TCR stimulus. Overall, these results indicate a direct, selective role for opioids in CD8+ T cell immune regulation via their ability to modulate cell responses through the opioid receptors and TCRs.

Footnotes

  • This work was supported by National Institutes of Health Grants R01 DA043253 (to A.D.L.), DP1 DA037993 (to A.D.L.), T32 AI089474 (to C.M.), T32 GM007250 (to B.L.B. and C.M.), F31 NS096857 (to B.L.B.), T32 NS077888 (to B.L.B.), TL1 RR024991 (to B.L.B.), DP1 DA037993-S1 (to A.C.-L.), and P30 AI036219 (to Case Western Reserve University/University Hospitals Cleveland Medical Center Center for AIDS Research).

  • The online version of this article contains supplemental material.

  • Received July 22, 2019.
  • Accepted December 26, 2019.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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Chronic Methadone Use Alters the CD8+ T Cell Phenotype In Vivo and Modulates Its Responsiveness Ex Vivo to Opioid Receptor and TCR Stimuli
Claire Mazahery, Bryan L. Benson, Angélica Cruz-Lebrón, Alan D. Levine
The Journal of Immunology January 22, 2020, ji1900862; DOI: 10.4049/jimmunol.1900862

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Chronic Methadone Use Alters the CD8+ T Cell Phenotype In Vivo and Modulates Its Responsiveness Ex Vivo to Opioid Receptor and TCR Stimuli
Claire Mazahery, Bryan L. Benson, Angélica Cruz-Lebrón, Alan D. Levine
The Journal of Immunology January 22, 2020, ji1900862; DOI: 10.4049/jimmunol.1900862
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Print ISSN 0022-1767        Online ISSN 1550-6606