Helios Controls a Limited Subset of Regulatory T Cell Functions

Sebastian, Mathew; Lopez-Ocasio, Maria; Metidji, Amina; Rieder, Sadiye Amcaoglu; Shevach, Ethan M; Thornton, Angela M

doi:10.4049/jimmunol.1501704

Cited by 173T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisCancer Immunotherapy and Biomarkers

Helios Controls a Limited Subset of Regulatory T Cell Functions

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Sebastian, Mathew, Lopez-Ocasio, Maria, Metidji, Amina, Rieder, Sadiye Amcaoglu, Shevach, Ethan M, Thornton, Angela M·2016·The Journal of Immunology

DOI 10.4049/jimmunol.1501704PMC PMC4685018

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Abstract

A subpopulation (60–70%) of Foxp3+ regulatory T cells (Tregs) in both mouse and man expresses the transcription factor Helios, but its role in Treg function is still unknown. We generated Treg-specific Helios-deficient mice to examine the function of Helios in Tregs. We show that the selective deletion of Helios in Tregs leads to slow, progressive systemic immune activation, hypergammaglobulinemia, and enhanced germinal center formation in the absence of organ-specific autoimmunity. Helios-deficient Treg suppressor function was normal in vitro, as well as in an in vivo inflammatory bowel disease model. However, Helios-deficient Tregs failed to control the expansion of pathogenic T cells derived from scurfy mice, failed to mediate T follicular regulatory cell function, and failed to control both T follicular helper cell and Th1 effector cell responses. In competitive settings, Helios-deficient Tregs, particularly effector Tregs, were at a disadvantage, indicating that Helios regulates effector Treg fitness. Thus, we demonstrate that Helios controls certain aspects of Treg-suppressive function, differentiation, and survival.

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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 [29]

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Nrf2 regulates CD4+ T cell–induced acute graft-versus-host disease in mice
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More Than Effects in Skin: Ultraviolet Radiation-Induced Changes in Immune Cells in Human Blood
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New Insights Into the Biology of CD8 Regulatory T Cells
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Coexpression of FOXP3 and a Helios isoform enhances the effectiveness of human engineered regulatory T cells
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New insights for regulatory T cell in lupus nephritis
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Intestinal CD4 Depletion in HIV / SIV Infection
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TIGIT and Helios Are Highly Expressed on CD4+ T Cells in Sézary Syndrome Patients
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Signaling Through gp130 Compromises Suppressive Function in Human FOXP3+ Regulatory T Cells
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Delivery of Rapamycin Using In Situ Forming Implants Promotes Immunoregulation and Vascularized Composite Allograft Survival
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Altered regulatory T‐cell fractions and Helios expression in clinically isolated syndrome: clues to the development of multiple sclerosis
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TIGIT modulates sepsis-induced immune dysregulation in mice with preexisting malignancy
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The Roles of FOXO1 in Periodontal Homeostasis and Disease
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Co-expression of Foxp3 and Helios facilitates the identification of human T regulatory cells in health and disease
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miR-466a Targeting of TGF-β2 Contributes to FoxP3+ Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation
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Ets1 suppresses atopic dermatitis by suppressing pathogenic T cell responses
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Gut Commensal Segmented Filamentous Bacteria Fine-Tune T Follicular Regulatory Cells to Modify the Severity of Systemic Autoimmune Arthritis
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Increased CD4 + CD25 - Foxp3 + T cells in Chinese systemic lupus erythematosus: correlate with disease activity and organ involvement
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Loss of CD28 within CD4+ T cell subsets from cervical cancer patients is accompanied by the acquisition of intracellular perforin, and is further enhanced by NKG2D expression
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IL-18 is required for the TH1-adaptation of TREG cells and the selective suppression of TH17 responses in acute and chronic infections
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FOXP3 and Its Cofactors as Targets of Immunotherapies
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Helios represses megakaryocyte priming in hematopoietic stem and progenitor cells
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Treg cell plasticity as a driver of inflammation in spondyloarthritis and psoriasis
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Anti-TIGIT differentially affects sepsis survival in immunologically experienced versus previously naive hosts
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Association of peripheral NK cell counts with Helios+IFN-γ– Tregs in patients with good long-term renal allograft function
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Helios expression in regulatory T cells promotes immunosuppression, angiogenesis and the growth of leukemia cells in pediatric acute lymphoblastic leukemia
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Helios Deficiency Predisposes the Differentiation of CD4+Foxp3− T Cells into Peripherally Derived Regulatory T Cells
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FK506 and Lactobacillus acidophilus ameliorate acute graft-versus-host disease by modulating the T helper 17/regulatory T-cell balance
Beak, J.-A., Park, M.-J., Kim, S. Y., Jhun, J., Woo, J. S., Choi, J. W., Na, H. S., Lee, S. K., Choi, J. Y., & Cho, M. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03303-z · Cited by 15 · see citing works
Helios + Regulatory T cell frequencies are correlated with control of viral replication and recovery of absolute CD4 T cells counts in early HIV-1 infection
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Glucocorticoids Oppose Thymocyte Negative Selection by Inhibiting Helios and Nur77
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Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay
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CD25 + FoxP3 + Memory CD4 T Cells Are Frequent Targets of HIV Infection In Vivo
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Influenza virus infection selectively triggers the accumulation and persistence of more potent Helios‐expressing Foxp3+ regulatory T cells in the lungs
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FOXP3 and Tip60 Structural Interactions Relevant to IPEX Development Lead to Potential Therapeutics to Increase FOXP3 Dependent Suppressor T Cell Functions
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Construction of miRNA-target networks using microRNA profiles of CVB3-infected HeLa cells
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Helios+ and RORγt+ Treg populations are differentially regulated by MHCII, CD28, and ICOS to shape the intestinal Treg pool
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Dysregulated germinal center reaction with expanded T follicular helper cells in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy lymph nodes
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Differential depletion of total T cells and regulatory T cells and prolonged allotransplant survival in CD3Ɛ humanized mice treated with polyclonal anti human thymocyte globulin
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Helios expression and Foxp3 TSDR methylation of IFNy+ and IFNy- Treg from kidney transplant recipients with good long-term graft function
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Expression of Helios is required for the differentiation of activated/effector T regulatory cells (IRC11P.438)
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Helios Deficiency Predisposes the Differentiation of CD4+Foxp3− T Cells into Peripherally Derived Regulatory T Cells
Skadow, M. H., Penna, V. R., Galant-Swafford, J., Shevach, E. M., & Thornton, A. M. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900388 · Cited by 16 · see citing works
Self-citation
Helios: still behind the clouds
Thornton, A. M., & Shevach, E. M. (2019) · Immunology · doi:10.1111/imm.13115 · Cited by 101 · see citing works
Self-citation
A role for the transcription factor Helios in human CD4+CD25+ regulatory T cells
Getnet, D., Grosso, J. F., Goldberg, M. V., Harris, T., Yen, H., Bruno, T. C., Durham, N. M., Hipkiss, E. L., Pyle, K. J., & Wada, S. (2010) · Molecular Immunology · doi:10.1016/j.molimm.2010.02.001 · Cited by 248 · see citing works
Helios expression defines two distinct populations of Foxp3+ regulatory T cells
Thornton, A. M., Kilaru, G., Burr, P., Rieder, S. A., Muljo, S. A., & Shevach, E. M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.196.supp.125.6 · Cited by 7 · see citing works
Self-citation

Authors: Sebastian, M., Lopez-Ocasio, M., Metidji, A., Rieder, S. A., Shevach, E. M., & Thornton, A. M.
Affiliations: National Institutes of Health (US)
Corresponding author: Shevach, Ethan M
ORCID: Sebastian, Mathew
Lopez-Ocasio, Maria
Metidji, Amina
Shevach, Ethan M
Thornton, Angela M
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2016-01-01
Volume: 196
Issue: 1
Pages: 144-155
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.1501704
PMC: PMC4685018
OpenAlex: W2178643122
Cited by: 172
References: 46
Citations by year: 2026: 9 · 2025: 15 · 2024: 6 · 2023: 19 · 2022: 10 · 2021: 22 · 2020: 14 · 2019: 29 · 2018: 22 · 2017: 13 · 2016: 13
FWCI: 7.87
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute of Allergy and Infectious Diseases (Z01AI000959)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords: Helios, regulatory T cells, Foxp3, Treg suppressive function, systemic immune activation, hypergammaglobulinemia, germinal center formation, inflammatory bowel disease, scurfy mice, follicular regulatory T cells, T follicular helper cells
MeSH terms: Animals, Autoimmune Diseases, Cell Differentiation, Disease Models, Animal, DNA-Binding Proteins, Female, Hypergammaglobulinemia, Male, Mice, Inbred C57BL, Transcription Factors, Inflammatory Bowel Diseases, Autoimmunity, Mice, Knockout, Th1 Cells, Germinal Center, T-Lymphocytes, Regulatory, Mice, Ikaros Transcription Factor, Forkhead Transcription Factors

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Helios Controls a Limited Subset of Regulatory T Cell Functions

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