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The Journal of Immunology, 2002, 169: 6580-6587.
Copyright © 2002 by The American Association of Immunologists

Increased Nonobese Diabetic Th1:Th2 (IFN-{gamma}:IL-4) Ratio Is CD4+ T Cell Intrinsic and Independent of APC Genetic Background1

Syuichi Koarada, Yuehong Wu, Grace Olshansky and William M. Ridgway2

Division of Rheumatology and Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

Autoreactive CD4+ T cells play a major role in the pathogenesis of autoimmune diabetes in nonobese diabetic (NOD) mice. We recently showed that the non-MHC genetic background controlled enhanced entry into the IFN-{gamma} pathway by NOD vs B6.G7 T cells. In this study, we demonstrate that increased IFN-{gamma}, decreased IL-4, and decreased IL-10 production in NOD T cells is CD4 T cell intrinsic. NOD CD4+ T cells purified and stimulated with anti-CD3/anti-CD28 Abs generated greater IFN-{gamma}, less IL-4, and less IL-10 than B6.G7 CD4+ T cells. The same results were obtained in purified NOD.H2b vs B6 CD4+ T cells, demonstrating that the non-MHC NOD genetic background controlled the cytokine phenotype. Moreover, the increased IFN-{gamma}:IL-4 cytokine ratio was independent of the genetic background of APCs, since NOD CD4+ T cells generated increased IFN-{gamma} and decreased IL-4 compared with B6.G7 CD4+ T cells, regardless of whether they were stimulated with NOD or B6.G7 APCs. Cell cycle analysis showed that the cytokine differences were not due to cycle/proliferative differences between NOD and B6.G7, since stimulated CD4+ T cells from both strains showed quantitatively identical entry into subsequent cell divisions (shown by CFSE staining), although NOD cells showed greater numbers of IFN-{gamma}-positive cells with each subsequent cell division. Moreover, 7-aminoactinomycin D and 5-bromo-2'-deoxyuridine analysis showed indistinguishable entry into G0/G1, S, and G2/M phases of the cell cycle for both NOD and B6.G7 CD4+ cells, with both strains generating IFN-{gamma} predominantly in the S phase. Therefore, the NOD cytokine effector phenotype is CD4+ T cell intrinsic, genetically controlled, and independent of cell cycle machinery.




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