Altered Th1 cell differentiation programming by CIITA deficiency.
CD4 T cell differentiation is a complex process affected by many transcription factors interacting in a tightly regulated manner. We have previously shown that CIITA-deficient mouse Th1 cells expressed Th2-type cytokines, while IFN-gamma expression was normal. In this study, we show that CIITA-deficient Th1 cells contain three distinct populations: cells secreting IL-4 alone, IFN-gamma alone, and both IL-4 and IFN-gamma together. This novel phenotype is stable over multiple rounds of stimulation in the presence of Th1-inducing factors. CIITA-deficient Th1 cells require TCR-mediated signaling to express Th2 cytokines, and this occurs with similar kinetics as wild-type Th2 cells. Both GATA-3 and IL-4 appear to be required for CIITA-deficient Th1 cells to express Th2-type cytokines. Interestingly, however, CIITA-deficient Th1 cells can produce IL-4 in the absence of exogenous IL-4. Introducing either CIITA or antisense GATA-3 during Th1 differentiation partially reduces Th2-type cytokine expression. With the exception of Th2-type cytokine expression, Th1 differentiation occurs normally in the absence of CIITA, as measured by expression of T-bet, IL-12Rbeta2, IL-18Ralpha, and IFN-gamma. Therefore, CIITA plays a key role to repress Th2-type cytokine expression as naive CD4 T cells differentiate toward the Th1 lineage.
Patel
Dipak R
DR
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Kaplan
Mark H
MH
Chang
Cheong-Hee
CH
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D050990:GATA3 Transcription Factor; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology; D015848:Interleukin-5 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D000949:Histocompatibility Antigens Class II; D018793:Interleukin-13; D015848:Interleukin-5; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma