Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE
Gregory D. Gregory, … , Susan Winandy, Melissa A. Brown
Gregory D. Gregory, … , Susan Winandy, Melissa A. Brown
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1327-1336. https://doi.org/10.1172/JCI27227.
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Research Article Immunology

Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE

Abstract

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-γ– 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 VA 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.

Authors

Gregory D. Gregory, Shveta S. Raju, Susan Winandy, Melissa A. Brown

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Figure 1

MC-derived IL-4 enhances the severity of EAE by promoting the generation of MOG35–55 -specific IFN-γ–expressing Th1 cells.

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MC-derived IL-4 enhances the severity of EAE by promoting the generatio...
(A) Diagram of the MC reconstitution protocol. MCs were generated by in vitro differentiation and transferred i.v. to MC-deficient W/Wv mice. (B) Mice were immunized with MOG35–55 peptide to induce EAE and monitored daily for clinical signs of paralysis. Mean clinical scores were determined daily (n = 5 per group). Squares, WT littermate controls; triangles, W/Wv; inverted triangles, W/Wv + IL-4–/– MC; circles, W/Wv + CD40L–/– MC. W/Wv and W/Wv + IL-4–/– MC mice exhibited significantly reduced EAE severity compared with WT littermate controls (P < 0.01). (C) WT, W/Wv, and W/Wv mice reconstituted with B6 or IL-4–/– BMMCs were perfused at 11 days after immunization, and flow cytometric analysis of CNS-infiltrating CD44hi CD4 T cells was performed. Numbers in quadrants represent the percentage of CD4 T cells; numbers in parenthesis indicate the percentage of CD4 T cells that are CD44hi. (D) Antigen-specific CD4+ T cell responses were measured by intracellular cytokine staining for IFN-γ after a brief in vitro restimulation of splenocytes with MOG35–55 peptide. *P < 0.05 versus WT; **P < 0.01 versus W/Wv + WT. For reconstitution in C and D, B6-derived BMMCs were used as controls for IL-4–/– BMMCs, whereas WBB6-F1/J-Kit+/Kit+ WT littermates were used as controls for W/Wv mice.