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Δ9-Tetrahydrocannabinol (THC) Impairs CD8+ T Cell-Mediated Activation of Astrocytes

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Abstract

CD8+ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8+ T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8+ T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10+, MCP-1+, and IL-6+ astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8+ T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8+ T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8+ T cell responses that contribute to stimulation of astrocytes.

Treatment with THC can abate CD8+ T cell-dependent neuroinflammatory processes by inhibiting CD8+ cell differentiation into effector cells, suppressing CD8+ effector cell function, and reducing activation of astrocytes by CD8+ T cell-derived inflammatory cytokines.

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Acknowledgements

We would like thank Dr. Bill Atchison and the University of Puerto Rico, Ponce for enabling Karina Matos-Fernandez to participate in and contribute to this research. The authors would also like to thank Jiajun Zhou, for formatting figures in preparation for article submission and Mrs. Kimberly Hambleton, for assistance in the submission of this article.

Funding

This work was supported by the National Institute on Drug Abuse Grants DA047180 and National Institute of Environmental Health Sciences Training Grants T32-ES007255 and R25-ES025060.

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Authors and Affiliations

  1. Michigan State University, East Lansing, MI, USA

    Joseph E. Henriquez, Anthony P. Bach, Karina M. Matos-Fernandez, Robert B. Crawford & Norbert E. Kaminski

  2. Department of Pharmacology and Toxicology, East Lansing, MI, USA

    Joseph E. Henriquez & Norbert E. Kaminski

  3. Institute for Integrative Toxicology, Michigan State University, 1129 Farm Lane, Rm 165G, Food Safety and Toxicology Building, East Lansing, MI, 48824, USA

    Joseph E. Henriquez, Robert B. Crawford & Norbert E. Kaminski

  4. Center for Research on Ingredient Safety, East Lansing, MI, USA

    Anthony P. Bach & Norbert E. Kaminski

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  1. Joseph E. Henriquez
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Henriquez, J.E., Bach, A.P., Matos-Fernandez, K.M. et al. Δ9-Tetrahydrocannabinol (THC) Impairs CD8+ T Cell-Mediated Activation of Astrocytes. J Neuroimmune Pharmacol 15, 863–874 (2020). https://doi.org/10.1007/s11481-020-09912-z

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