title: Δ9-tetrahydrocannabinol suppresses cytotoxic T lymphocyte function independent of CB1 and CB 2, disrupting early activation events.
abstract: Previously, CD8(+) T cells were found to be a sensitive target for suppression by Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in a murine model of influenza infection. To study the effect of Δ(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 (CB(1)) and 2 (CB(2)) in Δ(9)-THC-mediated CTL response modulation, mice null for both receptors were used (CB(1)                                   (-/-)CB(2)                                   (-/-)). Δ(9)-THC suppressed CTL function independent of CB(1) and CB(2) as evidenced by reduction of (51)Cr release by CTL generated from CB(1)                                   (-/-)CB(2)                                   (-/-) mice. Furthermore, viability in CD4(+) and CD8(+) cells was reduced in a concentration-dependent manner with Δ(9)-THC, independent of CB(1) and CB(2), but no effect of Δ(9)-THC on proliferation was observed, suggesting that Δ(9)-THC decreases the number of T cells initially activated. Δ(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 CB(1)                                   (-/-)CB(2)                                   (-/-) mice. Furthermore, Δ(9)-THC synergized with the calcium ionophore, ionomycin, to increase CD69 expression on both CD4(+) and CD8(+) cells. In addition, without stimulation, Δ(9)-THC increased CD69 expression in CD8(+) cells from CB(1)                                   (-/-)CB(2)                                   (-/-) and WT mice. Overall, these results suggest that CB(1) and CB(2) are dispensable for Δ(9)-THC-mediated suppression and that perturbation of Ca(2+) signals during T cell activation plays an important role in the mechanism by which Δ(9)-THC suppresses CTL function.
authors.affiliation: Cell and Molecular Biology Program, East Lansing, USA.
authors.forename: Peer W F
authors.initials: PW
authors.lastname: Karmaus
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Barbara L F
authors.initials: BL
authors.lastname: Kaplan
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002860:Chromium Radioisotopes; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007371:Interferon-gamma / Q000494:pharmacology; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects* / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002860:Chromium Radioisotopes; D013759:Dronabinol; D007371:Interferon-gamma; D037181:Lectins, C-Type; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099192:CD69 Antigens