CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like syndrome, and defective IL-10 expression from CD4 lymphocytes

doi:10.1016/j.jaci.2006.10.007

Journal of Allergy and Clinical Immunology

Volume 119, Issue 2, February 2007, Pages 482-487

https://doi.org/10.1016/j.jaci.2006.10.007 Get rights and content

Background

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) results in systemic autoimmunity from birth and can be caused by mutations in the transcription factor forkhead box P3 (FOXP3).

Objective

To determine if Foxp3 is required for the generation of IL-10–expressing T regulatory cells.

Methods

CD4 lymphocytes were isolated from patients with IPEX-like syndromes and activated with antibodies to CD3 and CD46 to generate IL-10–expressing T regulatory cells.

Results

We describe a patient with clinical manifestations of IPEX that had a normal Foxp3 gene, but who had CD25 deficiency due to autosomal recessive mutations in this gene. This patient exhibited defective IL-10 expression from CD4 lymphocytes, whereas a Foxp3-deficient patient expressed normal levels of IL-10.

Conclusion

These data show that CD25 deficiency results in an IPEX-like syndrome and suggests that although Foxp3 is not required for normal IL-10 expression by human CD4 lymphocytes, CD25 expression is important.

Clinical implications

Any patient with features of IPEX but with a normal Foxp3 gene should be screened for mutations in the IL-2 receptor subunit CD25.

Section snippets

CD4 lymphocyte isolation and activation

PBMCs were obtained using Ficoll-Paque (Amersham, Piscataway, NJ) and CD4 lymphocytes isolated with magnetic beads (Miltenyi Biotec, Auburn, Calif) under an Institutional Review Board–approved human studies protocol (Washington University, St Louis, Mo). Cells were activated with plate-bound antibodies to CD3 (OKT3, American Type Tissue Collection) and CD46 (Tra2-10) with human IL-2 or human IL-15 (eBioscience, San Diego, Calif), or with 10 ng/mL phorbol 12-myristate 13-acetate and 1 μmol/L

CD25 expression, but not Foxp3, is required for IL-10 production

To test whether Foxp3 expression was required for IL-10 production from human CD4 lymphocytes, 2 patients with syndromes consistent with IPEX were analyzed. One patient had a known FOXP3 coding sequence mutation (FOXP3^–),³ and the second patient had a normal Foxp3 coding sequence (Foxp3⁺, described). CD4 lymphocytes were isolated and stimulated with antibodies to CD3 and CD46, or CD3 and CD28 in the presence of IL-2. As shown in Fig 1, A, the Foxp3^– patient expressed levels of IL-10 comparable

Discussion

Herein we describe a patient with an IPEX-like syndrome with a normal Foxp3 gene but with a deficiency in CD25. He carries a single base pair insertion of one allele of his CD25 gene and a second allele with a substitution resulting in a stop codon. Analysis of CD25 expression from parental lymphocytes shows approximately half the amount of CD25 on the surface during T-cell activation, supporting the notion that each is heterozygous at the CD25 locus. Importantly, the proliferative defect of

References (17)

T.A. Chatila
Role of regulatory T cells in human diseases
J Allergy Clin Immunol
(2005)
J.A. Bluestone et al.
Natural versus adaptive regulatory T cells
Nat Rev Immunol
(2003)
T.A. Chatila et al.
JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome
J Clin Invest
(2000)
C.L. Bennett et al.
The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3
Nat Genet
(2001)
E. Gambineri et al.
Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis
Curr Opin Rheumatol
(2003)
M.G. Roncarolo et al.
Type 1 T regulatory cells
Immunol Rev
(2001)
H. Groux et al.
A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis
Nature
(1997)
C. Kemper et al.
Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype
Nature
(2003)

There are more references available in the full text version of this article.

Cited by (342)

Single cell characterization of blood and expanded regulatory T cells in autoimmune polyendocrine syndrome type 1
2024, iScience
Immune tolerance fails in autoimmune polyendocrine syndrome type 1 (APS-1) because of AIRE mutations. We have used single cell transcriptomics to characterize regulatory T cells (Tregs) sorted directly from blood and from in vitro expanded Tregs in APS-1 patients compared to healthy controls. We revealed only CD52 and LTB (down) and TXNIP (up) as consistently differentially expressed genes in the datasets. There were furthermore no large differences of the TCR-repertoire of expanded Tregs between the cohorts, but unique patients showed a more restricted use of specific clonotypes. We also found that in vitro expanded Tregs from APS-1 patients had similar suppressive capacity as controls in co-culture assays, despite expanding faster and having more exhausted cells. Our results suggest that APS-1 patients do not have intrinsic defects in their Treg functionality, and that their Tregs can be expanded ex vivo for potential therapeutic applications.
Engineering nanoparticle therapeutics for food allergy
2024, Journal of Allergy and Clinical Immunology
Food allergy is a growing public health issue among children and adults that can lead to life-threatening anaphylaxis following allergen exposure. The criterion standard for disease management includes food avoidance and emergency epinephrine administration because current allergen-specific immunotherapy treatments are limited by adverse events and unsustained desensitization. A promising approach to remedy these shortcomings is the use of nanoparticle-based therapies that disrupt disease-driving immune mechanisms and induce more sustained tolerogenic immune pathways. The pathophysiology of food allergy includes multifaceted interactions between effector immune cells, including lymphocytes, antigen-presenting cells, mast cells, and basophils, mainly characterized by a T_H2 cell response. Regulatory T cells, T_H1 cell responses, and suppression of other major allergic effector cells have been found to be major drivers of beneficial outcomes in these nanoparticle therapies. Engineered nanoparticle formulations that have shown efficacy at reducing allergic responses and revealed new mechanisms of tolerance include polymeric-, lipid-, and emulsion-based nanotherapeutics. This review highlights the recent engineering design of these nanoparticles, the mechanisms induced by them, and their future potential therapeutic targets.
Expanding IPEX: Inborn Errors of Regulatory T Cells
2023, Rheumatic Disease Clinics of North America
Effect of Boswellic acids on T cell proliferation and activation
2023, International Immunopharmacology
Boswellic acids have been recognized as anti-inflammatory and immunomodulatory agents with potentials to control autoimmune and inflammatory diseases. However, their effects on T cell proliferation and activation are not fully elucidated. In this study, we investigated effects of individual compounds including β-Boswellic acids (β-BA), 11-keto-β-Boswellic acid (β-KBA), 3-O-acetyl β-Boswellic acids (β-ABA), and 3-O-acetyl-11-keto-β-Boswellic acid (β-AKBA) on human peripheral blood mononuclear cells (PBMCs) and their potential role in modulating immune responses. We showed that β-BA, KBA, and AKBA at a 0.025 µM concentration significantly reduced T cell proliferation without inducing cytotoxicity, however, ABA showed cytotoxic effects at this concentration. β-BA and KBA showed significantly reduced T cell proliferation at 0.05 µM concentration without cytotoxic effects. Interestingly, we found that AKBA at 0.025 µM concentration significantly reduced CD25 expression on both CD4⁺ and CD8⁺ T cells without cytotoxic effects. Additionally, β-BA reduced CD25 expression on both CD4⁺ and CD8⁺ T cells at 0.05 µM concentration with no cytotoxicity. In this study, we determined the optimum concentration of each of these compounds that have the potential to reduce T cell activation without cytotoxic effects. Our findings show that both β-BA and AKBA have the ability to inhibit T cell proliferation and activation without inducing cytotoxicity. Further investigations are required to fully understand the mechanisms underlying these effects and the potential therapeutic benefits of these compounds in different autoimmune and inflammatory settings.
Inborn Errors of Immunity and Autoimmune Disease
2023, Journal of Allergy and Clinical Immunology: In Practice
Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.
Type 1 diabetes and inborn errors of immunity: Complete strangers or 2 sides of the same coin?
2023, Journal of Allergy and Clinical Immunology
Type 1 diabetes (T1D) is a polygenic disease and does not follow a mendelian pattern. Inborn errors of immunity (IEIs), on the other hand, are caused by damaging germline variants, suggesting that T1D and IEIs have nothing in common. Some IEIs, resulting from mutations in genes regulating regulatory T–cell homeostasis, are associated with elevated incidence of T1D. The genetic spectrum of IEIs is gradually being unraveled; consequently, molecular pathways underlying human monogenic autoimmunity are being identified. There is an appreciable overlap between some of these pathways and the genetic variants that determine T1D susceptibility, suggesting that after all, IEI and T1D are 2 sides of the same coin. The study of monogenic IEIs with a variable incidence of T1D has the potential to provide crucial insights into the mechanisms leading to T1D. These insights contribute to the definition of T1D endotypes and explain disease heterogeneity. In this review, we discuss the interconnected pathogenic pathways of autoimmunity, β-cell function, and primary immunodeficiency. We also examine the role of environmental factors in disease penetrance as well as the circumstantial evidence of IEI drugs in preventing and curing T1D in individuals with IEIs, suggesting the repositioning of these drugs also for T1D therapy.

View all citing articles on Scopus

Supported by National Institutes of Health grant R01-AI37618 (J.P.A.), R01-AI065617 (T.C.), the Washington University Rheumatology Postdoctoral Training Grant (A.A.C.), the Abbott Scholar Award in Rheumatology Research (J.W.V.), and the Children's Research Institute (S.T.R., J.W.V.)

Disclosure of potential conflict of interest: J. W. Verbsky has received an Abbott Scholar Award. The rest of the authors have declared that they have no conflict of interest.

View full text

Basic and clinical immunologyCD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like syndrome, and defective IL-10 expression from CD4 lymphocytes

Background

Objective

Methods

Results

Conclusion

Clinical implications

Section snippets

CD4 lymphocyte isolation and activation

CD25 expression, but not Foxp3, is required for IL-10 production

Discussion

Role of regulatory T cells in human diseases

J Allergy Clin Immunol

Natural versus adaptive regulatory T cells

Nat Rev Immunol

JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome

J Clin Invest

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3

Nat Genet

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis

Curr Opin Rheumatol

Type 1 T regulatory cells

Immunol Rev

A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis

Nature

Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype

Nature

Basic and clinical immunology
CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like syndrome, and defective IL-10 expression from CD4 lymphocytes