Cutting Edge: Ikaros Is a Regulator of Th2 Cell Differentiation

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 Ikarosnull mice cultured under Th2-skewing conditions express the Th1 cytokine IFN-γ 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 Ikarosnull 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.

Ikaros is required to survive positive selection and to maintain clonal diversity during T-cell development in the thymus

“…32,33 These results confirm successful expression of a functional DN-IkTg in thymocytes and T cells.…”

Helios Deficiency Has Minimal Impact on T Cell Development and Function

“…In particular, most of the defects associated with Ikaros deficiency are not detected in Helios-null mice (i.e., lack of fetal T cell development, reduced cellularity in the adult thymus, increases in DN4 and CD4 single-positive thymocyte populations, reduced ␥␦ T cells, increased Th1 and impaired Th2 differentiation, T cell hyperproliferation, and T cell transformation; see Refs. 14,22,25). Thus, Helios is clearly not required for Ikaros-dependent function in T cells and is not sufficient to sustain T cell development alone.…”

“…Loss of Ikaros also leads to a decreased ␥␦ T cell pool, as well as altered commitment to the CD4 and CD8 lineages (14,23,24). In mature T cells, Ikaros appears to suppress Th1 polarization (25) and to limit proliferation in response to signaling in both CD4…”

Expression of Helios in Peripherally Induced Foxp3+ Regulatory T Cells

“…Helios is a member of the Ikaros family of transcription factors, whose five members contain conserved Cterminal zinc finger motifs, which allow homodimeric or heterodimeric interactions between family members (6,7). Through such dimerization, Helios may alter the function of Ikaros (8)(9)(10), which has been reported to influence T helper differentiation (11)(12)(13). In the steady state, Helios expression is largely restricted to Foxp3 + Treg (5,(14)(15)(16).…”