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Δ9-Tetrahydrocannabinol Suppresses Cytotoxic T Lymphocyte Function Independent of CB1 and CB2, Disrupting Early Activation Events

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Abstract

Previously, CD8+ T cells were found to be a sensitive target for suppression by Δ9-tetrahydrocannabinol (Δ9-THC) in a murine model of influenza infection. To study the effect of Δ9-THC on CD8+ cytotoxic T lymphocytes (CTL), an allogeneic model of MHC I mismatch was used to elicit CTL. In addition, to determine the requirement for the cannabinoid receptors 1 (CB1) and 2 (CB2) in Δ9-THC-mediated CTL response modulation, mice null for both receptors were used (CB1 −/−CB2 −/−). Δ9-THC suppressed CTL function independent of CB1 and CB2 as evidenced by reduction of 51Cr release by CTL generated from CB1 −/−CB2 −/− mice. Furthermore, viability in CD4+ and CD8+ cells was reduced in a concentration-dependent manner with Δ9-THC, independent of CB1 and CB2, but no effect of Δ9-THC on proliferation was observed, suggesting that Δ9-THC decreases the number of T cells initially activated. Δ9-THC increased expression of the activation markers, CD69 in CD8+ cells and CD25 in CD4+ cells in a concentration-dependent manner in cells derived from WT and CB1 −/−CB2 −/− mice. Furthermore, Δ9-THC synergized with the calcium ionophore, ionomycin, to increase CD69 expression on both CD4+ and CD8+ cells. In addition, without stimulation, Δ9-THC increased CD69 expression in CD8+ cells from CB1 −/−CB2 −/− and WT mice. Overall, these results suggest that CB1 and CB2 are dispensable for Δ9-THC-mediated suppression and that perturbation of Ca2+ signals during T cell activation plays an important role in the mechanism by which Δ9-THC suppresses CTL function.

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Acknowledgements

The authors would like to thank Mr. Robert Crawford for excellent technical assistance with flow cytometer and Mrs. Kimberly Hambleton for assistance with submission of the manuscript.

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Authors and Affiliations

  1. Cell and Molecular Biology Program, East Lansing, USA

    Peer W. F. Karmaus & Norbert E. Kaminski

  2. Microbiology and Molecular Genetics, East Lansing, USA

    Weimin Chen

  3. Center for Integrative Toxicology, East Lansing, USA

    Peer W. F. Karmaus, Weimin Chen, Barbara L. F. Kaplan & Norbert E. Kaminski

  4. Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824, USA

    Barbara L. F. Kaplan & Norbert E. Kaminski

  5. Center for Integrative Toxicology, Pharmacology and Toxicology, Cell and Molecular Biology Program, 315 Food Safety and Toxicology Building, East Lansing, USA

    Norbert E. Kaminski

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  1. Peer W. F. Karmaus
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  2. Weimin Chen
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  3. Barbara L. F. Kaplan
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  4. Norbert E. Kaminski
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Correspondence to Norbert E. Kaminski.

Additional information

Support: NIH Grants RO1DA12740 and RO1DA07908

Δ9-tetrahydrocannabinol was provided by NIDA

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Karmaus, P.W.F., Chen, W., Kaplan, B.L.F. et al. Δ9-Tetrahydrocannabinol Suppresses Cytotoxic T Lymphocyte Function Independent of CB1 and CB2, Disrupting Early Activation Events. J Neuroimmune Pharmacol 7, 843–855 (2012). https://doi.org/10.1007/s11481-011-9293-4

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  • DOI: https://doi.org/10.1007/s11481-011-9293-4

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