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Review
. 2019 Nov;158(3):161-170.
doi: 10.1111/imm.13115. Epub 2019 Oct 13.

Helios: still behind the clouds

Angela M Thornton  1 , Ethan M Shevach  1
Affiliations
Review

Helios: still behind the clouds

Angela M Thornton et al. Immunology. 2019 Nov.

Abstract

Regulatory T (Treg) cells are a subset of CD4+ T cells that are critical for the maintenance of self-tolerance. The forkhead box transcription factor Foxp3 is a master regulator for the Treg phenotype and function and its expression is essential in Treg cells, as the loss of Foxp3 results in lethal autoimmunity. Two major subsets of Treg cells have been described in vivo; thymus-derived Treg (tTreg) cells that develop in the thymus and peripherally induced Treg (pTreg) cells that are derived from conventional CD4+ Foxp3- T cells and are converted in peripheral tissues to cells that express Foxp3 and acquire suppressive ability. The transcription factor Helios, a member of the Ikaros transcription factor family, is expressed in 60-70% of Treg cells in both mouse and man, and is believed to be a marker of tTreg cells. In this review, we discuss the role and function of Helios in Treg cells, the controversy surrounding the use of Helios as a marker of tTreg cells, and how Helios controls specific aspects of the Treg cell program.

Keywords: autoimmunity; regulation/suppression; regulatory T cells; transcription factors.

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Conflict of interest statement

The authors have no financial conflicts of interest.

Figures

Figure 1
Figure 1
Ikaros transcription factor family. The exons for each protein are outlined with the conserved zinc fingers of the DNA‐binding domains in blue and the conserved zinc fingers of the dimerization domain in red. The epitope recognized by the monoclonal antibody 22F6 is indicated by the yellow triangle and the loxP sites used for targeted deletion are shown flanking exon 8 of Helios.
Figure 2
Figure 2
Helios expression. Thymocytes and splenocytes from C57BL/6 mice were analyzed by flow cytometry for the expression of Foxp3 and Helios. Top: CD4− CD8− double‐negative (DN) thymocytes were subdivided based on CD44 and CD25 expression (DN1: CD44+ CD25−, DN2: CD44+ CD25+, DN3: CD44− CD25+, DN4: CD44− CD25−). Bottom: CD4+  CD8− single‐positive thymocytes (left) and CD4+ CD8− splenocytes (right).
Figure 3
Figure 3
Analysis of heterozygous Foxp3 females. (a) CD4+ Foxp3+ thymocytes or splenocytes from 2‐ or 5‐month‐old Ikzf2fl/fl × Foxp3wt/ YFP ‐Cre mice were analyzed by flow cytometry for YFP expression, a reporter for the Helios‐deficient cells. (b) YFP − (wild‐type; WT) or YFP + (knockout; KO) CD4+ Foxp3+ Treg cells were analyzed for CD44 and CD62L to calculate the percent of eTreg cells defined as CD44+ CD62L−.
Figure 4
Figure 4
Expression of neuropilin‐1 (Nrp1) on regulatory T (Treg) cells is partially dependent on GARP‐derived transforming growth factor‐β (TGF‐β). CD4+ Foxp3+ cells from wild‐type (WT) or GARP fl/fl × CD4‐Cre (knockout; KO) mice were analyzed for expression of Helios and Nrp1.
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