Helios: still behind the clouds

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 À 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.

Molecular Insights Into Regulatory T-Cell Adaptation to Self, Environment, and Host Tissues: Plasticity or Loss of Function in Autoimmune Disease

“…The potential for the cooperation of miRNAs and FOXP3 enabling tight control of Treg phenotype and function is mechanistically plausible. We and several other groups have demonstrated that miRNAs, such as miR-155 and FOXP3, cooperate to coordinately repress other key genes in Treg and other cell types ( 77 ), including SATB1 ( 34 ) ( Figure 3A ), and have identified a number of other candidate miRNAs involved in reinforcing the Treg genotype. We observe that a common miRNA/FOXP3-mediated molecular switch is able to regulate several key genes, and this forms a negative feedforward component shaping part of the FOXP3 GRN.…”

“…In contrast, peripheral Treg arise from FOXP3-negative naïve T cells which do not express FOXP3 until stimulated in the presence of cytokines and transcriptional activators, which turn on the FOXP3 gene. The molecular steps required to set up and stabilize the expression of FOXP3 in the thymus, including a key role played by SATB1 ( 31 – 33 ) and Helios ( 34 – 39 ), may be distinct from those inducing FOXP3 in the periphery. Recently, the role of Helios in Treg ontology was further elucidated as deficiency in Helios results in preferential differentiation into pTreg ( 35 ).…”

Helios Expression in Tumor-Infiltrating Lymphocytes Correlates with Overall Survival of Advanced Gastric Cancer Patients

“…Ikaros, the founding member of this family, is mainly expressed in most hematopoietic cells, whereas Helios is expressed primarily in T-lineage cells and early multipotential precursor cells [ 23 , 24 ]. Helios is expressed in 60–70% of Treg cells in both mice and humans [ 25 ]. However, in mice, specific deletion of Helios in Treg cells developed systemic autoimmunity; in contrast, specific deletion in CD4 cells lacks an autoimmune phenotype [ 26 ].…”

The functional and phenotypic diversity of single T-cell infiltrates in human colorectal cancer as correlated with clinical outcome

“…7a). The transcription factor Helios (encoded by the gene IKZF2) has been proposed to mark thymically-derived Tregs although currently controversial [51][52][53] . In contrast, Helios -Tregs within the CD4_pTreg cluster exhibited a distinct phenotype (CD161 + , CD69 + , LAG3 + , CD38 hi ) and shared genes (IL26, KLRB1, IKZF3, LAG3) with peripherally-derived CD4 + FOXP3 -T conventional (Tconv) cells, known as peripherally-derived Tregs (pTregs) [54][55][56][57] (Figs.…”