Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype.
These studies were conducted to determine the effects of oxidative stress on human T cell differentiation and polarization into Th1 or Th2 phenotypes. Highly purified naive CD4+ T cells were isolated from PBMC of healthy, nonatopic donors. CD4+ T cells were stimulated with anti-CD3 and anti-CD28 mAb in the presence or absence of oxidative stress as supplied by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), which generates a low level of superoxide anion. Increases in cellular superoxide were observed by exposure to DMNQ. Exposure of unpolarized CD4+ T cells to IL-12 or IL-4 resulted in a Th1 or Th2 phenotype, respectively. T cells stimulated in the absence of polarizing cytokines secreted modest amounts of IFN-gamma and TNF-alpha. Cells stimulated in the continuous presence of 5 microM DMNQ, displayed a marked up-regulation in Th2 cytokines, including IL-4, IL-5, and IL-13, but not the Th1 cytokine IFN-gamma. Th2 responses were blunted by concomitant exposure to thiol antioxidants. Long-term exposure of T cells to DMNQ resulted in growth of cells expressing CCR4, and a decrease in cells expressing CXCR3, indicating phenotypic conversion to Th2 cells. These results suggest that oxidative stress favors a Th2-polarizing condition.
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8884, USA.
Miranda R
MR
King
Anisa S
AS
Ismail
Laurie S
LS
Davis
David R
DR
Karp
D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D019169:Jurkat Cells; D009285:Naphthoquinones / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
D016207:Cytokines; D009285:Naphthoquinones; D019707:Receptors, Chemokine; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C063002:2,3-dimethoxy-1,4-naphthoquinone