Stable inhibitory activity of regulatory T cells requires the transcription factor Helios
Open accessAbstract
How T cells maintain their identity: Although best known for their pathogen-fighting prowess, T lymphocytes also ensure that the immune response does not run amok. A subset of T cells called regulatory T cells (T regs ) performs this function by, for example, making sure T cells only attack pathogens and not self. T cells can exhibit plasticity in their functions in the face of an inflammatory stimulus. Kim et al. sought to identify the molecules that ensure the stable maintenance of T regs . Using genetically modified mice, they found that both CD4 + and CD8 + T regs require the transcription factor Helios to stably maintain their identity. Science , this issue p. 334
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Loss of IKZF2 can shift TRegs toward a pro-inflammatory state such that they secrete IL-2 and IFN-γ and behave like tumor-fighting Teff-like cells.
“However, its loss can shift tRegs toward a pro-inflammatory state such they secrete il-2 and iFN-γ and behave like tumor-fighting teff-like cells (Kim et al. 2015;Nakagawa et al. 2016).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Kim et al. 2015
In the paper’s section labeled Abstract (page unavailable), Helios-deficient mouse CD4 Tregs acquire an effector phenotype and produce IFN-γ under inflammatory conditions. The paper discusses reduced IL-2 responsiveness, not IL-2 secretion. It proposes tumor-antigen-specific Treg-to-effector conversion as a possibility for cancer immunotherapy, but does not show that the cells fight tumors. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTGFB1 promotes the expression of IKZF2 (also known as Helios), a transcription factor governing the suppressive function of CD8+ and CD4+ T cells.
“and promotes the expression of IKZF2 (also known as Helios), a transcription factor governing the suppressive function of CD8+ and CD4+ T cells,54”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [54]
The paper identifies IKZF2 as Helios and describes its role in maintaining the suppressive phenotype of CD4+ and CD8+ regulatory T cells (passages 2 and 4; page unavailable). The passages do not establish that TGFB1 promotes IKZF2 expression; a search for TGF-β induction of Helios did not find support for that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIKZF2 mediates STAT5 activation for survival of CD8 Tregs and preventing terminal T cell differentiation.
“Additionally, IKZF2 mediates STAT5 activation for survival of CD8 Tregs and preventing terminal T cell differentiation [72].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [72]
Acute pharmacological degradation of Helios recapitulates the phenotype of genetic loss of Ikzf2 in Tregs.
“Notably, the preferential Helios degrader ALV2 destabilized the anergic phenotype of regulatory Tregs, consistent with previously reported phenotypes of Ikzf2−/− Tregs5,6,29, demonstrating that acute pharmacological degradation of Helios recapitulates the phenotype of genetic loss of Ikzf2 in Tregs.”
From Acute pharmacological degradation of Helios destabilizes regulatory T cells (2021) · cites this paper as [6]
Helios is critical for maintaining the identity, anergic phenotype, and suppressive activity of regulatory T cells.
“The zinc finger transcription factor Helios is critical for maintaining the identity, anergic phenotype, and suppressive activity of regulatory T cells.”
From Acute pharmacological degradation of Helios destabilizes regulatory T cells (2021) · cites this paper as [6]
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“However, its loss can shift tRegs toward a pro-inflammatory state such they secrete il-2 and iFN-γ and behave like tumor-fighting teff-like cells (Kim et al. 2015; Nakagawa et al. 2016). iKZF2 has therefore been linked to t cell exhaustion, a state marked by reduced proliferation, decreased…”
- Authors
- Kim, H.-J., Barnitz, R. A., Kreslavsky, T., Brown, F. D., Moffett, H., Lemieux, M. E., Kaygusuz, Y., Meissner, T., Holderried, T. A. W., Chan, S., Kastner, P., Haining, W. N., & Cantor, H.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Bioinfo, Plantagenet, Canada.
- Centre National de la Recherche Scientifique (FR)
- Broad Institute (US)
- Corresponding author
- Cantor, Harvey
- ORCID
- Venue
- Science
- Published
- 2015-10-16
- Volume
- 350
- Issue
- 6258
- Pages
- 334-339
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4627635
- OpenAlex
- W2191493147
- Cited by
- 441
- References
- 25
- Citations by year
- 2026: 37 · 2025: 44 · 2024: 41 · 2023: 43 · 2022: 51 · 2021: 43 · 2020: 36 · 2019: 41 · 2018: 35 · 2017: 35 · 2016: 33 · 2015: 2
- FWCI
- 17.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- NIH (R01AI37562)
- Arthritis National Research Foundation
- LeRoy Schecter Research Foundation
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- regulatory T cells, Helios, Foxp3, STAT5 signaling, immune homeostasis, autoimmunity, CD8+ regulatory T cells, CD4+ regulatory T cells, inflammation, transcription factors
- MeSH terms
- Animals, DNA-Binding Proteins, Kidney, Liver, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Transgenic, Pancreas, Transcription Factors, Autoimmunity, Gene Expression, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, STAT5 Transcription Factor, Mice, Forkhead Transcription Factors
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