Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9

Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9–Expressing Cells Publisher Pubmed

Rao G¹ ; Mack CD¹ ; Nguyen T^{1, 2} ; Wong N¹ ; Payne K¹ ; Worley L^{1, 2} ; Gray PE^{3, 4} ; Wong M^{5, 6} ; Hsu P^{5, 6} ; Stormon MO⁵ ; Preece K⁷ ; Suan D¹ ; Osullivan M⁸ ; Blincoe AK⁹ Show All Authors

Rao G¹
Mack CD¹
Nguyen T^{1, 2}
Wong N¹
Payne K¹
Worley L^{1, 2}
Gray PE^{3, 4}
Wong M^{5, 6}
Hsu P^{5, 6}
Stormon MO⁵
Preece K⁷
Suan D¹
Osullivan M⁸
Blincoe AK⁹
Sinclair J⁹
Okada S¹⁰
Hambleton S^{11, 12}
Arkwright PD¹³
Boztug K^{14, 15, 16}
Stepensky P¹⁷
Cooper MA¹⁸
Bezrodnik L^{19, 20}
Nadeau KC^{21, 22}
Abolhassani H^{23, 24}
Abraham RS²⁵
Seppanen MRJ^{26, 27, 28}
Beziat V^{29, 30, 31}
Bustamante J^{29, 30, 31, 32}
Forbes Satter LR³³
Leiding JW^{34, 35}
Meyts I^{36, 37, 38}
Jouanguy E^{30, 31, 32}
Boissondupuis S^{29, 30, 31}
Uzel G³⁹
Puel A^{29, 30, 31}
Casanova JL^{29, 30, 31, 40, 41}
Tangye SG^{1, 2}
Ma CS^{1, 2}

Show Affiliations

1. Garvan Institute of Medical Research, Darlinghurst, Australia
2. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Sydney, Australia
3. Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, Australia
4. School of Women's and Children's Health, UNSW Sydney, Sydney, Australia
5. Children's Hospital at Westmead, Westmead, Australia
6. Faculty of Medicine, University of Sydney, Sydney, Australia
7. John Hunter Children's Hospital, Newcastle, Australia
8. Immunology Department, Fiona Stanley Hospital, Murdoch, Australia
9. Starship Children's Hospital, Auckland, New Zealand
10. Department of Pediatrics, of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
11. Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
12. Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
13. Lydia Becker Institute for Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
14. St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
15. Medical University of Vienna, Department of Paediatrics and Adolescent Medicine, Vienna, Austria
16. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
17. Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Hebrew University Medical Centre, Jerusalem, Israel
18. Department of Pediatrics, Division of Rheumatology/Immunology, Washington University School of Medicine, St Louis, Mo, United States
19. Grupo de Inmunologia–Instituto Multidisciplinario de Investigaciones en Patologias Pediatricas (IMIPP-CONICET), Hospital de Ninos “Dr. Ricardo Gutierrez, ” Buenos Aires, Argentina
20. Center for Clinical Immunology, Buenos Aires, Argentina
21. Sean N. Parker Center for Allergy and Asthma Research, Stanford, Calif, United States
22. Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, Calif, United States
23. Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
24. Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
25. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, United States
26. Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
27. Rare Diseases Center and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
28. ERN-RITA Core Center, RITAFIN, Helsinki, Finland
29. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, U1163, France
30. Imagine Institute, Universite Paris Cite, Paris, France
31. St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States
32. Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France
33. 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, United States
34. Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, Md, United States
35. Institute for Clinical and Translational Research and the Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St Petersburg, Fla, United States
36. Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium
37. Department of Pediatrics, Division of Inborn Errors of Immunity, University Hospitals Leuven, Leuven, Belgium
38. FWO Vlaanderen, Brussels, Belgium
39. Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md, United States
40. Howard Hughes Medical Institute, New York, NY, United States
41. Department of Pediatrics, Necker Hospital for Sick Children, Paris, France

Source: Journal of Allergy and Clinical Immunology Published:2025

Abstract

Background: CD4+ T cells play essential roles in adaptive immunity. Distinct CD4+ T-cell subsets—TH1, TH2, TH17, TH22, 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 TH9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human TH9 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, TH9 polarizing condition), and the combination of IL-21, IL-23, IL-6, IL-1β, and TGF-β (ie, TH17 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. © 2024 American Academy of Allergy, Asthma & Immunology

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Style	Citing Format
MLA	Rao G, et al.. "Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9–Expressing Cells." Journal of Allergy and Clinical Immunology, vol. 155, no. 4, 2025, pp. 1161-1178.
APA	Rao G, Mack CD, Nguyen T, Wong N, Payne K, Worley L, Gray PE, Wong M, Hsu P, Stormon MO, Preece K, Suan D, Osullivan M, Blincoe AK, Sinclair J, Okada S, Hambleton S, Arkwright PD, Boztug K, ... Ma CS (2025). Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9–Expressing Cells. Journal of Allergy and Clinical Immunology, 155(4), 1161-1178.
Chicago	Rao G, Mack CD, Nguyen T, Wong N, Payne K, Worley L, Gray PE, et al.. "Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9–Expressing Cells." Journal of Allergy and Clinical Immunology 155, no. 4 (2025): 1161-1178.
Harvard	Rao G et al. (2025) 'Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9–Expressing Cells', Journal of Allergy and Clinical Immunology, 155(4), pp. 1161-1178.
Vancouver	Rao G, Mack CD, Nguyen T, Wong N, Payne K, Worley L, et al.. Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9–Expressing Cells. Journal of Allergy and Clinical Immunology. 2025;155(4):1161-1178.
BibTex	@article{ author = {Rao G and Mack CD and Nguyen T and Wong N and Payne K and Worley L and Gray PE and Wong M and Hsu P and Stormon MO and Preece K and Suan D and Osullivan M and Blincoe AK and Sinclair J and Okada S and Hambleton S and Arkwright PD and Boztug K and Stepensky P and Cooper MA and Bezrodnik L and Nadeau KC and Abolhassani H and Abraham RS and Seppanen MRJ and Beziat V and Bustamante J and Forbes Satter LR and Leiding JW and Meyts I and Jouanguy E and Boissondupuis S and Uzel G and Puel A and Casanova JL and Tangye SG and Ma CS}, title = {Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9–Expressing Cells}, journal = {Journal of Allergy and Clinical Immunology}, volume = {155}, number = {4}, pages = {1161-1178}, year = {2025} }
RIS	TY - JOUR AU - Rao G AU - Mack CD AU - Nguyen T AU - Wong N AU - Payne K AU - Worley L AU - Gray PE AU - Wong M AU - Hsu P AU - Stormon MO AU - Preece K AU - Suan D AU - Osullivan M AU - Blincoe AK AU - Sinclair J AU - Okada S AU - Hambleton S AU - Arkwright PD AU - Boztug K AU - Stepensky P AU - Cooper MA AU - Bezrodnik L AU - Nadeau KC AU - Abolhassani H AU - Abraham RS AU - Seppanen MRJ AU - Beziat V AU - Bustamante J AU - Forbes Satter LR AU - Leiding JW AU - Meyts I AU - Jouanguy E AU - Boissondupuis S AU - Uzel G AU - Puel A AU - Casanova JL AU - Tangye SG AU - Ma CS TI - Inborn Errors of Immunity Reveal Molecular Requirements for Generation and Maintenance of Human Cd4+ Il-9–Expressing Cells JO - Journal of Allergy and Clinical Immunology VL - 155 IS - 4 SP - 1161 EP - 1178 PY - 2025 ER -

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