Magnitude of stimulation dictates the cannabinoid-mediated differential T cell response to HIVgp120.
Approximately 25% of immunocompromised HIV patients smoke marijuana for its putative therapeutic benefit. The goal of these studies was to test the hypothesis that marijuana-derived cannabinoids have immunomodulatory effects on HIV antigen-specific T cell effector function. A surrogate mouse model to induce polyclonal T cell responses against HIV(gp120) was established. THC, a marijuana-derived cannabinoid, suppressed or enhanced mouse CD8(+) T cell proliferation and the gp120-specific CTL response depending on the magnitude of the IFN-γ response. To determine the molecular mechanisms by which cannabinoids differentially modulate T cell responses, P/I or anti-CD3/CD28 antibodies were used for stimulation, and another marijuana-derived cannabinoid, CBD, was also investigated. THC or CBD suppressed or enhanced IFN-γ and IL-2 production by mouse splenocytes under optimal or suboptimal stimulation, respectively. Similar differential effects of cannabinoids on cytokine production were also observed on nuclear translocation of NFAT and with human PBMCs in response to P/I stimulation. However, THC and CBD elevated intracellular calcium, regardless of the stimulation level with P/I, suggesting that the cannabinoid-induced calcium increase provides an appropriate signal for activation in suboptimally stimulated T cells but an anergic-like signal as a result of excessive calcium in optimally stimulated T cells. Overall, these data demonstrate differential modulation by cannabinoids of a HIV antigen-specific response and identify a possible mechanism responsible for this effect.
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
Weimin
W
Chen
Barbara L F
BL
Kaplan
Schuyler T
ST
Pike
Lauren A
LA
Topper
Nicholas R
NR
Lichorobiec
Steven O
SO
Simmons
Ram
R
Ramabhadran
Norbert E
NE
Kaminski
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D013759:Dronabinol / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D007155:Immunologic Factors / Q000494:pharmacology*; D056747:Immunomodulation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*
D016207:Cytokines; D015699:HIV Envelope Protein gp120; D007155:Immunologic Factors; D013759:Dronabinol