Exposure of Human CD4 T Cells to IL-12 Results in Enhanced TCR-Induced Cytokine Production, Altered TCR Signaling, and Increased Oxidative Metabolism

• Published in: PloS one 2016-06, Vol.11 (6), p.e0157175
• Main Authors: Vacaflores, Aldo, Chapman, Nicole M, Harty, John T, Richer, Martin J, Houtman, Jon C D
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; AKT protein; Autoimmune diseases; Biology and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; Cytokines; Cytokines - immunology; Exposure; Female; Genetic aspects; Health aspects; Humans; Interferon; Interleukin 10; Interleukin 12; Interleukin 13; Interleukin 4; Interleukin-12 - pharmacology; Lck protein; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - immunology; Lymphocytes; Lymphocytes T; Male; Medicine and Health Sciences; Metabolism; Middle Aged; Oxidation-Reduction - drug effects; Oxidative metabolism; p38 Mitogen-Activated Protein Kinases - immunology; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - immunology; Physiological aspects; Post-transcription; Proto-Oncogene Proteins c-akt - immunology; Receptors, Antigen, T-Cell - immunology; Research and Analysis Methods; Signal Transduction - drug effects; Signal Transduction - immunology; Signaling; Stimulation; T cell antigen receptors; T cell receptors; T cells; T-cell receptor; Transcription, Genetic - drug effects; Transcription, Genetic - immunology; Tumor necrosis factor; Tumor necrosis factor-α; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0157175

Human CD4 T cells are constantly exposed to IL-12 during infections and certain autoimmune disorders. The current paradigm is that IL-12 promotes the differentiation of naïve CD4 T cells into Th1 cells, but recent studies suggest IL-12 may play a more complex role in T cell biology. We examined if exposure to IL-12 alters human CD4 T cell responses to subsequent TCR stimulation. We found that IL-12 pretreatment increased TCR-induced IFN-γ, TNF-α, IL-13, IL-4 and IL-10 production. This suggests that prior exposure to IL-12 potentiates the TCR-induced release of a range of cytokines. We observed that IL-12 mediated its effects through both transcriptional and post-transcriptional mechanisms. IL-12 pretreatment increased the phosphorylation of AKT, p38 and LCK following TCR stimulation without altering other TCR signaling molecules, potentially mediating the increase in transcription of cytokines. In addition, the IL-12-mediated enhancement of cytokines that are not transcriptionally regulated was partially driven by increased oxidative metabolism. Our data uncover a novel function of IL-12 in human CD4 T cells; specifically, it enhances the release of a range of cytokines potentially by altering TCR signaling pathways and by enhancing oxidative metabolism.