Delta(9)-Tetrahydrocannabinol Suppresses Cytotoxic T Lymphocyte Function Independent of CB1 and CB2, Disrupting Early Activation Events

作者：Karmaus Peer W F; Chen Weimin; Kaplan Barbara L F; Kaminski Norbert E^*

来源：Journal of Neuroimmune Pharmacology, 2012, 7(4): 843-855.

DOI：10.1007/s11481-011-9293-4

• Delta(9)-tetrahydrocannabinol
• Cannabinoid receptors
• Cytotoxic T lymphocytes
• Immune modulation
• Ca2+
• T cell activation

Previously, CD8(+) T cells were found to be a sensitive target for suppression by Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in a murine model of influenza infection. To study the effect of Delta(9)-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 Delta(9)-THC-mediated CTL response modulation, mice null for both receptors were used (CB1 -/-CB2 (-/-)). Delta(9)-THC suppressed CTL function independent of CB1 and CB2 as evidenced by reduction of Cr-51 release by CTL generated from CB1 -/-CB2 (-/-) mice. Furthermore, viability in CD4(+) and CD8(+) cells was reduced in a concentration-dependent manner with Delta(9)-THC, independent of CB1 and CB2, but no effect of Delta(9)-THC on proliferation was observed, suggesting that Delta(9)-THC decreases the number of T cells initially activated. Delta(9)-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, Delta(9)-THC synergized with the calcium ionophore, ionomycin, to increase CD69 expression on both CD4(+) and CD8(+) cells. In addition, without stimulation, Delta(9)-THC increased CD69 expression in CD8(+) cells from CB1 -/-CB2 (-/-) and WT mice. Overall, these results suggest that CB1 and CB2 are dispensable for Delta(9)-THC-mediated suppression and that perturbation of Ca2+ signals during T cell activation plays an important role in the mechanism by which Delta(9)-THC suppresses CTL function.

• 出版日期2012-12