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. 2009 Jan 15;182(2):741-5.
doi: 10.4049/jimmunol.182.2.741.

Cutting edge: Ikaros is a regulator of Th2 cell differentiation

Mary R Quirion  1 , Gregory D Gregory, Sarah E Umetsu, Susan Winandy, Melissa A Brown
Affiliations

Cutting edge: Ikaros is a regulator of Th2 cell differentiation

Mary R Quirion et al. J Immunol. .

Abstract

Ikaros, a hematopoietic transcription factor, has well defined effects on early lymphocyte development in the bone marrow and thymus. In this study we demonstrate that Ikaros is a positive regulator of Th2 cytokine gene expression in peripheral T cells. CD4+ T cells from naive Ikaros(null) mice cultured under Th2-skewing conditions express the Th1 cytokine IFN-gamma and have reduced IL-4, IL-5, and IL-13 expression. Ikaros directly associates with several Th2 locus regulatory regions in naive CD4+ T cells. The decreased ability to express Th2 cytokines in Ikaros(null)T cells corresponds with histone 3 hypoacetylation across the Th2 cytokine locus as well as decreased GATA3 and cMaf and increased T-bet and STAT1 expression. These data support a model whereby Ikaros directly activates Th2 gene expression by promoting local chromatin accessibility during CD4+ T cell differentiation and also acts indirectly to regulate expression of Th2- and Th1-specific transcription factors.

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Conflict of interest statement

Disclosures

The authors have no financial conflict of interest.

Figures

FIGURE 1
FIGURE 1
Ikaros is required for proper Th2 differentiation. A–C, Cytokine expression in CD4+ T cells cultured for 5 days under nonskewing (A), Th1-polarizing (B), or Th2-polarizing (C) conditions. D, Cytokine mRNA expression assessed by semiquantitative PCR. HPRT, Hypoxanthine phosphoribosyltransferase. E, IL-4 expression in wild-type (WT) T cells after infection at 20 h or after 5 days in Th2-differentiating cultures with a dominant negative Ik-7 retrovirus. Infected cells were isolated using anti-H-2Kk MACS beads before analysis. These results are representative of six independent experiments.
FIGURE 2
FIGURE 2
Ikaros binds to type 2 cytokine locus regulatory regions. A, Schematic of the Th2 locus on murine chromosome 11. B, Regulatory VISTA analysis of the Th2 locus identified non-coding regions of homology and putative binding site clusters for STAT, GATA, and Ikaros (tick marks above plot). C, Ikaros binding analysis using ChIP assay. These results are the compilation of three real-time runs with each primer set for each of three independent ChIP assays. HS, Hypersensitive site; IE, intron enhancer; LCR, locus control region; M20, anti-Ikaros Ab; TC, total chromatin; VAE, VA enhancer.
FIGURE 3
FIGURE 3
Ikaros deficiency results in hypoacetylation of the Th2 cytokine locus. Histone H3 acetylation (K9/K14) was compared between naive (A) and Th2-differentiated (B) wild-type (Ik+/+) and Ikarosnull (Ik−/−) CD4+ T cells. Significant differences at the Th2 locus were observed in wild-type and Ikarosnull T cells; p < 0.05 at all sites basally; p < 0.001 at all sites except IL-4 intron enhancer (IE), p < 0.05. No significant differences were observed at the Rad50B site. These results are the compilation of three real-time amplifications with each primer set for each of three independent ChIP assays. Ac-H3, H3 acetylation; VaE, VA enhancer.
FIGURE 4
FIGURE 4
Ikaros deficiency results in significant changes in the expression of lineage-specific transcription factors. Semiquantitative real-time analysis comparing cDNA levels of lineage-specific transcription factors between wild-type and Ikarosnull T cells performed subsequent to 5 days under Th2-polarizing conditions. HPRT, Hypoxanthine phosphoribosyltransferase.
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