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Research ArticleInflammation, Immunopharmacology, and Asthma

Interferon-α–Mediated Activation of T Cells from Healthy and HIV-Infected Individuals Is Suppressed by Δ9-Tetrahydrocannabinol

Joseph E. Henriquez, Michael D. Rizzo, Robert B. Crawford, Peter Gulick and Norbert E. Kaminski
Journal of Pharmacology and Experimental Therapeutics October 2018, 367 (1) 49-58; DOI: https://doi.org/10.1124/jpet.118.250308
Joseph E. Henriquez
Departments of Pharmacology and Toxicology (J.E.H., N.E.K.), Cell and Molecular Biology (M.D.R.), and Osteopathic Medicine (P.G.), and Institute for Integrative Toxicology (J.E.H., M.D.R., R.B.C., N.E.K.), Michigan State University, East Lansing, Michigan
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Michael D. Rizzo
Departments of Pharmacology and Toxicology (J.E.H., N.E.K.), Cell and Molecular Biology (M.D.R.), and Osteopathic Medicine (P.G.), and Institute for Integrative Toxicology (J.E.H., M.D.R., R.B.C., N.E.K.), Michigan State University, East Lansing, Michigan
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Robert B. Crawford
Departments of Pharmacology and Toxicology (J.E.H., N.E.K.), Cell and Molecular Biology (M.D.R.), and Osteopathic Medicine (P.G.), and Institute for Integrative Toxicology (J.E.H., M.D.R., R.B.C., N.E.K.), Michigan State University, East Lansing, Michigan
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Peter Gulick
Departments of Pharmacology and Toxicology (J.E.H., N.E.K.), Cell and Molecular Biology (M.D.R.), and Osteopathic Medicine (P.G.), and Institute for Integrative Toxicology (J.E.H., M.D.R., R.B.C., N.E.K.), Michigan State University, East Lansing, Michigan
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Norbert E. Kaminski
Departments of Pharmacology and Toxicology (J.E.H., N.E.K.), Cell and Molecular Biology (M.D.R.), and Osteopathic Medicine (P.G.), and Institute for Integrative Toxicology (J.E.H., M.D.R., R.B.C., N.E.K.), Michigan State University, East Lansing, Michigan
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    Fig. 1.

    Healthy and HIV+ donors have comparable T-cell composition. (A) T cells were identified as CD3+ lymphocytes, and then classified as helper or cytotoxic T lymphocytes based upon the surface expression of CD4 and CD8, respectively. Memory T cells were identified as CD45RO+ and nonmemory T cells were identified as CD45RO− for both CD4+ and CD8+ T cells. (B) HIV+ donors possessed CD4+ and CD8+ T-cell numbers that were comparable to those of the healthy donors, and comparable memory (CD45RO+)/nonmemory (CD45RO−) cell composition. FSC-A, forward scatter area; RO−, CD45RO−; RO+, CD45RO+; SSC-A, side scatter area.

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    Fig. 2.

    T cells from healthy and HIV+ donors exhibit different profiles of IFNΑR2 expression and IFNα-induced STAT1 phosphorylation, which is suppressed by THC. PBMCs from healthy and HIV+ donors were isolated by Ficoll Paque density gradient centrifugation and used for the determination of either IFNΑR2 surface expression or IFNα-induced STAT1 phosphorylation (pSTAT1). (A) IFNAR2 expression was quantified by flow cytometry using the mean fluorescence intensity (MFI). For pSTAT1, PBMCs were treated with either vehicle (0.03% EtOH) or THC (1, 5, or 10 µM) in 0.03% EtOH for 30 minutes before stimulation with 100 U/ml IFNα for 30 minutes. (B) Representative experiment of IFNα-mediated pSTAT1 induction and THC (10 µM)-mediated suppression in T cells from a healthy donor. The effects of THC on IFNα-pSTAT1 induction in: total (C), memory (D) and nonmemory (E) CD4+ T cells; and total (F), memory (G), and nonmemory (H) CD8+ T cells. For IFNΑR2 expression, asterisks indicate statistically significant differences (*P < 0.05) of MFI in HIV compared with type-matched T cells from healthy donors. For pSTAT1, asterisks indicate statistically significant differences of the treatment with the HIV status–matched VC (0 THC) (*P < 0.05; **P < 0.01; ***P < 0.001). Daggers indicate statistically significant differences of treatment-matched groups between T cells from healthy and HIV+ donors (†P < 0.05) (two-way analysis of variance with Bonferroni multiple-comparisons post-test). SSC-A, side scatter area.

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    Fig. 3.

    THC suppresses IFNα-induced expression of IL-7Rα mRNA in T cells from healthy donors but differentially affects IFNα-induced surface expression of IL-7Rα in T cells from healthy vs. HIV+ T donors. (A) To determine the effects of IFNα and THC on IL-7Rα mRNA expression, T cells were purified from healthy donors, and treated with either vehicle (0.03% EtOH) or various concentrations of THC (1, 5, or 10 µM) for 30 minutes. After treatment, cells were stimulated with IFNα (100 U/ml), incubated for 48 hours, and harvested for quantification of IL-7Rα mRNA levels by real-time quantitative PCR. For the determination of IL-7Rα surface expression, PBMCs from healthy and HIV+ donors were isolated through Ficoll Paque density gradient centrifugation and either immediately stained for CD3, CD4, CD8, CD45RO, and IL-7Rα (D0) or treated with THC and IFNα, as described above, and measured for IL-7Rα expression after 48 hours. (B) Example of IFNα-mediated IL-7Rα expression and THC (10 µM)-mediated suppression in a healthy donor. The effects of THC on the expression level [mean fluorescence intensity (MFI)] of IL-7Rα in T cells from healthy and HIV+ donors in total (C), memory (D), and nonmemory (E) CD4+ cells; and total (F), memory (G), and nonmemory (H) CD8+ cells. Asterisks indicate statistically significant differences of the treatment with the HIV status–matched VC (0 THC) (*P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001). Daggers indicate statistically significant differences of treatment-matched groups between Healthy and HIV+ T cells (†P ≤ 0.05; ††P ≤ 0.01) (two-way analysis of variance with Bonferroni multiple-comparisons post-test). D0, day 0; SSC-A, side scatter area.

  • Fig. 4.
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    Fig. 4.

    THC suppresses IFNα-mediated augmentation of IL-7–induced STAT5 phosphorylation. PBMCs from healthy and HIV+ donors were isolated through Ficoll Paque density gradient centrifugation. Cells were either: 1) immediately used for the detection of IL-7–induced pSTAT5 (D0) by treating with IL-7 (10 ng/ml) for 15 minutes then rapidly fixed; or 2) treated with either vehicle (0.03% EtOH) or various concentrations of THC (1, 5, or 10 µM) for 30 minutes, stimulated with IFNα (100 U/ml), incubated for 48, and then used for the detection of IL-7–induced pSTAT5, as described above. (A) Representative experiment of IL-7Rα–induced pSTAT5- and THC (10 µM)-mediated suppression in a healthy donor. (B) Levels [mean fluorescence intensity (MFI)] of pSTAT5 in T cells was determined by flow cytometry on day 0. The effects of THC on the IL-7–induced pSTAT5 level after IFNα stimulation of T cells from healthy and HIV+ donors in: total (C), memory (D), and nonmemory (E) CD4+ cells; and total (F), memory (G), and nonmemory (H) CD8+ cells. Asterisks indicate statistically significant differences between treatments with the HIV status–matched VC (0 THC) (*P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001). Daggers indicate statistically significant differences of treatment-matched groups between healthy and HIV+ T cells (†P ≤ 0.05) (two-way analysis of variance with Bonferroni multiple-comparisons post-test). D0, day 0; SSC-A, side scatter area.

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    Fig. 5.

    IL-7 augmented CD3/CD28/IFNα-induced T-cell proliferation is suppressed by THC. PBMCs from healthy and HIV+ donors were isolated through Ficoll Paque density gradient centrifugation. Cells were stained with violet CellTrace dye and then treated with either vehicle (0.03% EtOH) or various concentrations of THC (1, 5, or 10 µM) for 30 minutes. After treatment, cells were stimulated with IFNα (100 U/ml) and anti-CD3 and anti-CD28 antibodies (2.5 μg/ml each) for 48 hours, treated with IL-7 (10 ng/ml) or vehicle (endotoxin-free H2O), and incubated for another 48 hours before harvesting. T-cell proliferation is represented as the DI, as determined by the FlowJo proliferation tool. (A) Representative experiment of IL-7–mediated augmentation of T-cell proliferation in CD3/CD28/IFNα-stimulated T cells and THC (10 µM)-mediated suppression in a healthy donor. The effects of treatment with IFNα and IL-7 on anti-CD3/CD28-mediated T-cell proliferation in CD4+ (B) and CD8+ (C) T cells from healthy and HIV+ donors. The effect of IL-7 stimulation on total CD3+ T-cell composition and between memory (CD45RO+) and nonmemory (CD45RO−) cells in CD4+ (D) and CD8+ (E) T cells. The effects of THC on the IL-7–induced augmentation of CD3/CD28/IFNα-induced proliferation of T cells from healthy and HIV+ donors in total (F), memory (G), and nonmemory (H) CD4+ cells; and total (I), memory (J), and nonmemory (K) CD8+ cells. Pound signs indicate statistically significant differences in the proliferation of IL-7 treated T cells compared to T cells without IL-7 treatment (#P ≤ 0.05). Asterisks indicate statistically significant differences of the treatment with the HIV status–matched VC (0 THC or D0) (*P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001). Daggers indicate statistically significant differences of treatment-matched groups between healthy and HIV+ T cells (†P ≤ 0.05; ††P ≤ 0.01) (two-way analysis of variance with Bonferroni multiple-comparisons post-test). D0, day 0; SSC-A, side scatter area.

Additional Files

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      1. Stimulation of T cells with IFN alpha reduces IFNAR2 expression of CD4+ cells and enhances expression on CD8+ T cells...

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Journal of Pharmacology and Experimental Therapeutics: 367 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 367, Issue 1
1 Oct 2018
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Research ArticleInflammation, Immunopharmacology, and Asthma

THC Suppresses T-Cell Activation by IFNα and IL-7

Joseph E. Henriquez, Michael D. Rizzo, Robert B. Crawford, Peter Gulick and Norbert E. Kaminski
Journal of Pharmacology and Experimental Therapeutics October 1, 2018, 367 (1) 49-58; DOI: https://doi.org/10.1124/jpet.118.250308

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Research ArticleInflammation, Immunopharmacology, and Asthma

THC Suppresses T-Cell Activation by IFNα and IL-7

Joseph E. Henriquez, Michael D. Rizzo, Robert B. Crawford, Peter Gulick and Norbert E. Kaminski
Journal of Pharmacology and Experimental Therapeutics October 1, 2018, 367 (1) 49-58; DOI: https://doi.org/10.1124/jpet.118.250308
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