Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE.
When exposed to a pathogen, a naive CD4(+) T cell is forced to make a cell fate decision that leads to a polarized population of Th1 IFN-gamma- or Th2 IL-4- producing cells. Although IL-4 has traditionally been considered a factor that promotes Th2 cell differentiation, recent evidence has demonstrated that the site and timing of IL-4 expression in an immune response determines its ultimate effects on CD4(+) T cell fate. Using a mast cell (MC) reconstitution model, we demonstrate that MC-derived IL-4 promoted Th1 responses in vivo. Furthermore, MCs from genetically disparate mouse strains varied in their potential for IL-4 expression. Independent of the activation mode, MCs from Th1-prone C57BL/6 mice exhibited a more robust Il4 response than did the Th2-prone strain Balb/c. The hierarchy of IL-4 expression potential was directly associated with the degree of basal chromatin accessibility at cis-regulatory elements conserved noncoding sequence-1 and V(A) enhancer within the Th2 locus. GATA1/2 and Ikaros, factors with opposing roles in chromatin remodeling, acted at these sites. We propose that GATA and Ikaros proteins coordinately fine-tune accessibility at the Il4 locus during development to variably regulate IL-4 expression. These events likely contribute to the genetically determined heterogeneity in Th1 responses that underlie susceptibility to many diseases.
Gregory
Gregory D
GD
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611-3010, USA.
Raju
Shveta S
SS
Winandy
Susan
S
Brown
Melissa A
MA
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000276:immunology*; D005260:Female; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D051740:Ikaros Transcription Factor / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D018417:Th1 Cells / Q000378:metabolism*
D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; C494689:Gata1 protein, mouse; C494712:Gata2 protein, mouse; D051740:Ikaros Transcription Factor; D015847:Interleukin-4