Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4⁺ IL-9–expressing cells - 03/04/25

Doi : 10.1016/j.jaci.2024.11.031

Geetha Rao, MSc ^a, Corinne D. Mack, PhD ^a, Tina Nguyen, PhD ^a,^b, Natalie Wong, BSc Hons ^a, Kathryn Payne, BSc Hons ^a, Lisa Worley, PhD ^a,^b, Paul E. Gray, MD, FRACP ^c,^d, Melanie Wong, MBBS, PhD, FRACP, FRCPA ^e,^f, Peter Hsu, FRACP, PhD ^e,^f, Michael O. Stormon, MBBS, FRACP ^e, Kahn Preece, MD ^g, Daniel Suan, MBBS, PhD ^a, Michael O’Sullivan, MBBS ^h, Annaliesse K. Blincoe, BHB, MBChB ⁱ, Jan Sinclair, MD ⁱ, Satoshi Okada, MD, PhD ^j, Sophie Hambleton, PhD ^k,^l, Peter D. Arkwright, FRCPCH, DPhil ^m, Kaan Boztug, MD ^n,^o,^p, Polina Stepensky, MD ^q, Megan A. Cooper, MD, PhD ^r, Liliana Bezrodnik, MD ^s,^t, Kari C. Nadeau, MD, PhD, FAAAAI ^u,^v, Hassan Abolhassani, MD, PhD ^w,^x, Roshini S. Abraham, PhD ^y, Mikko R.J. Seppänen, MD, PhD ^z,^aa,^bb, Vivien Béziat, PhD ^cc,^dd,^ee, Jacinta Bustamante, MD, PhD ^cc,^dd,^ee,^ff, Lisa R. Forbes Satter, MD ^gg, Jennifer W. Leiding, MD ^hh,ⁱⁱ, Isabelle Meyts, MD, PhD ^jj,^kk,^ll, Emmanuelle Jouanguy, PhD ^dd,^ee,^ff, Stéphanie Boisson-Dupuis, PhD ^cc,^dd,^ee, Gulbu Uzel, MD ^mm, Anne Puel, PhD ^cc,^dd,^ee, Jean-Laurent Casanova, MD, PhD ^cc,^dd,^ee,^nn,^oo, Stuart G. Tangye, PhD ^a,^b, Cindy S. Ma, PhD ^a,^b,^⁎
^a Garvan Institute of Medical Research, Darlinghurst, Australia
^b School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Sydney, Australia
^c Department of Immunology and Infectious Diseases, Sydney Children’s Hospital, Sydney, Australia
^d School of Women’s and Children’s Health, UNSW Sydney, Sydney, Australia
^e Children’s Hospital at Westmead, Westmead, Australia
^f Faculty of Medicine, University of Sydney, Sydney, Australia
^g John Hunter Children’s Hospital, Newcastle, Australia
^h Immunology Department, Fiona Stanley Hospital, Murdoch, Australia
ⁱ Starship Children’s Hospital, Auckland, New Zealand
^j Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
^k Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
^l Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
^m Lydia Becker Institute for Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
ⁿ St Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
^o Medical University of Vienna, Department of Paediatrics and Adolescent Medicine, Vienna, Austria
^p CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
^q Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Hebrew University Medical Centre, Jerusalem, Israel
^r Department of Pediatrics, Division of Rheumatology/Immunology, Washington University School of Medicine, St Louis, Mo
^s Grupo de Inmunología–Instituto Multidisciplinario de Investigaciones en Patologias Pediatricas (IMIPP-CONICET), Hospital de Niños “Dr. Ricardo Gutierrez,” Buenos Aires, Argentina
^t Center for Clinical Immunology, Buenos Aires, Argentina
^u Sean N. Parker Center for Allergy and Asthma Research, Stanford, Calif
^v Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, Calif
^w Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
^x Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
^y Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio
^z Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^aa Rare Diseases Center and Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^bb ERN-RITA Core Center, RITAFIN, Helsinki, Finland
^cc Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
^dd Imagine Institute, Université Paris Cité, Paris, France
^ee St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
^ff Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France
^gg Department of Pediatrics, Baylor College of Medicine, and Texas Children’s Hospital, William T. Shearer Center for Human Immunobiology, Department of Allergy, Immunology, and Retrovirology, Houston, Tex
^hh Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, Md
ⁱⁱ Institute for Clinical and Translational Research and the Cancer and Blood Disorders Institute, Johns Hopkins All Children’s Hospital, St Petersburg, Fla
^jj Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium
^kk Department of Pediatrics, Division of Inborn Errors of Immunity, University Hospitals Leuven, Leuven, Belgium
^ll FWO Vlaanderen, Brussels, Belgium
^mm Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
ⁿⁿ Howard Hughes Medical Institute, New York, NY
^oo Department of Pediatrics, Necker Hospital for Sick Children, Paris, France

^∗Corresponding author: Cindy S. Ma, PhD, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010 Australia.Garvan Institute of Medical Research384 Victoria StDarlinghurstNSW2010Australia

Abstract

Background

CD4⁺ T cells play essential roles in adaptive immunity. Distinct CD4⁺ T-cell subsets—T_H1, T_H2, T_H17, T_H22, T follicular helper, and regulatory T cells—have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9–producing T_H9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human T_H9 cells remain incompletely defined.

Objective

We sought to define signaling pathways that regulate IL-9 production by human CD4⁺ T cells.

Methods

Human naive and memory CD4⁺ T cells were cultured under different conditions, and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4⁺ T cells from a broad range of patients (n = 92) with pathogenic variants in key immune genes (n = 21) to differentiate into IL-9⁺ cells.

Results

We identified 2 culture conditions that yielded IL-9–expressing cells from naive CD4⁺ T cells and amplified IL-9 production by in vivo–generated memory CD4⁺ T cells: TGF-β plus IL-4 (ie, T_H9 polarizing condition), and the combination of IL-21, IL-23, IL-6, IL-1β, and TGF-β (ie, T_H17 polarizing condition). Combining these conditions had a synergistic effect in generating IL-9⁺CD4⁺ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signaling via the T-cell receptor and STAT5. Importantly, IL-9 induction was restrained by IFN-γ/STAT1 and IL-10.

Conclusions

Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4⁺ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.

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Key words : T_H9 cells, IL-9 expression, human CD4⁺ T-cell differentiation, cytokines, inborn errors of immunity

Abbreviations used : AD, CBA, CTV, DN, GOF, IBD, IEI, IRAK4, ITK, JAK, LOF, MAGT1, NF-κB, PBMC, ROR, SOCS3, STAT, TAE, TCR, Tfh, Treg

Plan

Methods

Human samples

CD4⁺ T-cell isolation

STAT activation

In vitro differentiation

Cell proliferation

Cytokine secretion and expression

Statistical analysis

Results

T_H9 and T_H17 polarizing conditions individually and synergistically induce IL-9 expression and secretion in human CD4⁺ T cells

IL-9 production by naive and memory CD4⁺ T cells after in vitro culture with T_H9 and/or T_H17 polarizing conditions is dependent on endogenous IL-2 and IL-4

IL-9 is predominantly produced by CCR4⁺CD4⁺ T cells but can be induced by all memory CD4⁺ T-cell subsets

T_H9 and T_H17 polarizing cultures operate via different STAT pathways

Induction of IL-9 expression in human naive CD4⁺ T cells is linked to cell division

Combination of IL-1β, TGF-β, and 2 STAT3-activating cytokines is sufficient to induce IL-9 expression

Molecular circuitry required for generating IL-9⁺ cells

Impaired TCR/IL-2 signaling impedes differentiation of human naive CD4⁺ T cells into IL-9⁺ cells

Regulation by canonical and noncanonical NF-κB pathway

STAT1 GOF and STAT3 LOF/dominant-negative variants compromise human IL-9 differentiation

IFN-γ and IL-10 signaling pathways negatively regulate IL-9 induction

Discussion

This article is part of a special issue entitled: Genetic Errors of Immunity published in the Journal of Allergy and Clinical Immunology.

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Vol 155 - N° 4

P. 1161-1178 - avril 2025 Retour au numéro

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Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4⁺ IL-9–expressing cells - 03/04/25

Abstract

Background

Objective

Methods

Results

Conclusions

Plan

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