Exposure of Human CD4 T Cells to IL-12 Results in Enhanced TCR-Induced Cytokine Production, Altered TCR Signaling, and Increased Oxidative Metabolism.
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.
Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.
Aldo
http://orcid.org/0000-0003-0670-620X
A
Vacaflores
Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.
Nicole M
NM
Chapman
Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.|Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
John T
JT
Harty
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
Martin J
MJ
Richer
Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.|Department of Internal Medicine, Division of Immunology, University of Iowa, Iowa City, Iowa, United States of America.
Jon C D
JC
Houtman
D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology*; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases