Impaired IL-4 production by CD8+ T cells in NOD mice is related to a defect of c-Maf binding to the IL-4 promoter.
CD8(+) T cells play an important role in the induction of the autoimmune response in non-obese diabetic (NOD) mice. Here we describe abnormalities in the control of cytokine production by NOD CD8(+) T cells. NOD CD8(+) T cells had an increased propensity to produce IFN-gamma upon TCR activation, in both adult and 2-week-old mice. NOD CD8(+) T cells had a reduced capacity to produce IL-4 in type 2 conditions compared to CD8(+) T cells from the diabetes-resistant strains BALB/c and C57BL/6. Both GATA-3 and c-Maf, two positive transactivators for IL-4 gene expression, were expressed in type 2 conditions at comparable levels in NOD CD8(+) T cells. The GATA-3 was functional since normal levels of IL-5 were produced and the IL-4 promoter was hyperacetylated in NOD CD8(+) T cells. In contrast, c-Maf failed to bind to its responsive element as determined by chromatin immunoprecipitation (ChIP) assay. These results suggest that NOD CD8(+) T cells possess an increased propensity to produce IFN-gamma and impaired c-Maf-dependent DNA binding activities in vivo that lead to reduced IL-4 production following TCR activation. These defects may facilitate the development of the autoimmune response by inducing an overall type 1-biased immune response in NOD mice.
Chen
Xiao-Ping
XP
Department of Immunology, University of Pittsburgh, Pittsburgh, USA.
Falkner
Dewayne H
DH
Morel
Penelope A
PA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D050990:GATA3 Transcription Factor; D015151:Immunoblotting; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D051257:Proto-Oncogene Proteins c-maf; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma