Δ9-Tetrahydrocannabinol treatment impairs CD8+ T cell differentiation into interferon gamma-competent CD45RO+ cells.

Abstract

Chronic human immunodeficiency virus (HIV) infection results in a persistent state of neuroinflammation, even with combined antiretroviral therapy. Neuroinflammation contributes to pathology termed HIV-associated neurocognitive disorder, which is exacerbated by interferon gamma (IFNγ)-producing CD8⁺ T cells in the central nervous system. Many people living with HIV self-report using Cannabis sativa to mitigate symptoms of chronic infection and side effects of treatment. C. sativa is composed of various phytocannabinoids, including Δ⁹-tetrahydrocannbinol (THC), which possesses immune-modulating properties. This study aims to determine whether C. sativa use by people living with HIV, and specifically THC, affects IFNγ secretion by CD8⁺ T cells. We found that HIV status does not influence T cell IFNγ responses, and C sativa use modestly reduces the average secretion of IFNγ by CD8⁺ T cells from HIV+ donors. Treatment of CD8⁺ T cells with THC and the selective cannabinoid receptor 2 agonist, JWH-015, reduced T-cell cytokine secretion, with THC eliciting greater suppression than cannabidiol. These results suggest that THC treatment does not directly impair IFNγ gene expression or protein production, as determined by polymerase chain reaction and flow cytometry. However, THC treatment impaired CD8⁺ T cell differentiation into IFNγ-competent CD45RO⁺ cells. These studies are of clinical relevance because reduction of CD8⁺ T-cell-derived IFNγ in the central nervous system may improve cognitive outcomes during HIV infection. Furthermore, these findings may be generalizable to other inflammatory diseases in which IFNγ-producing CD8⁺ T cells have been implicated. SIGNIFICANCE STATEMENT: Δ⁹-Tetrahydrocannbinol (THC) treatment reduces CD8⁺ T cell interferon gamma (IFNγ) secretion isolated from HIV- and HIV+ individuals. THC and the selective cannabinoid receptor 2 agonist, JWH-015, both reduced CD8⁺ T cell secretion of IFNγ, interleukin 2, and tumor necrosis factor α, suggesting the involvement of cannabinoid receptor 2. Although THC treatment does not suppress IFNγ mRNA or protein levels, it reduces the number of IFNγ-secreting cells by impairing CD8⁺ T-cell differentiation into IFNγ-competent CD45RO⁺ cells.