Cindy S Ma1, Natalie Wong2, Geetha Rao2, Danielle T Avery2, James Torpy2, Thomas Hambridge2, Jacinta Bustamante3, Satoshi Okada4, Jennifer L Stoddard5, Elissa K Deenick6, Simon J Pelham6, Kathryn Payne2, Stéphanie Boisson-Dupuis7, Anne Puel8, Masao Kobayashi4, Peter D Arkwright9, Sara Sebnem Kilic10, Jamila El Baghdadi11, Shigeaki Nonoyama12, Yoshiyuki Minegishi13, Seyed Alireza Mahdaviani14, Davood Mansouri14, Aziz Bousfiha15, Annaliesse K Blincoe16, Martyn A French17, Peter Hsu18, Dianne E Campbell18, Michael O Stormon18, Melanie Wong18, Stephen Adelstein19, Joanne M Smart20, David A Fulcher21, Matthew C Cook22, Tri Giang Phan6, Polina Stepensky23, Kaan Boztug24, Aydan Kansu25, Aydan İkincioğullari26, Ulrich Baumann27, Rita Beier28, Tony Roscioli29, John B Ziegler30, Paul Gray30, Capucine Picard3, Bodo Grimbacher31, Klaus Warnatz31, Steven M Holland32, Jean-Laurent Casanova33, Gulbu Uzel32, Stuart G Tangye34. 1. Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia. Electronic address: c.ma@garvan.org.au. 2. Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia. 3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France; Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France. 4. Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan. 5. Clinical Center, National Institutes of Health, Bethesda, Md. 6. Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia. 7. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY. 8. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France. 9. University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom. 10. Department of Pediatric Immunology, Uludag University Medical Faculty, Görükle, Bursa, Turkey. 11. Genetics Unit, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco. 12. Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan. 13. Division of Molecular Medicine, Institute for Genome Research, University of Tokushima, Tokushima, Japan. 14. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. 15. Clinical Immunology Unit, Pediatric Infectious Diseases Department, Averroes University Hospital, King Hasan II University, Casablanca, Morocco. 16. Starship Children's Hospital, Auckland, New Zealand. 17. Department of Clinical Immunology, Royal Perth Hospital, Perth, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia. 18. Children's Hospital at Westmead, Westmead, Australia. 19. Clinical Immunology, Royal Prince Alfred Hospital, Sydney, Australia. 20. Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Melbourne, Australia. 21. Department of Immunology, Westmead Hospital, University of Sydney, Westmead, Australia. 22. Australian National University Medical School, Australian National University, Acton, Australia; John Curtin School of Medical Research, Australian National University, Acton, Australia; Department of Immunology, Canberra Hospital, Canberra, Australia. 23. Pediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem, Israel. 24. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 25. Department of Pediatric Gastroenterology, Ankara University Medical School, Ankara, Turkey. 26. Department of Pediatric Immunology and Allergy, Ankara University Medical School, Ankara, Turkey. 27. Paediatric Pulmonology, Allergy and Neonatology, Hanover Medical School, Hannover, Germany. 28. Pediatric Haematology and Oncology, University Hospital Essen, Essen, Germany. 29. St Vincent's Clinical School, UNSW Australia, Melbourne, Australia; Kinghorn Centre for Clinical Genomics, Victoria St Darlinghurst, Darlinghurst, Australia; Department of Medical Genetics, Sydney Children's Hospital, Randwick, Australia. 30. Sydney Children's Hospital, Randwick, and School of Women's and Children's Health, University of New South Wales, Sydney, Australia. 31. Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany. 32. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 33. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France; Howard Hughes Medical Institute, New York, NY. 34. Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia. Electronic address: s.tangye@garvan.org.au.
Abstract
BACKGROUND: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. OBJECTIVE: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. METHODS: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. RESULTS: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. CONCLUSION: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.
BACKGROUND: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. OBJECTIVE: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. METHODS: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. RESULTS: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. CONCLUSION: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.
Authors: Cindy S Ma; Danielle T Avery; Anna Chan; Marcel Batten; Jacinta Bustamante; Stephanie Boisson-Dupuis; Peter D Arkwright; Alexandra Y Kreins; Diana Averbuch; Dan Engelhard; Klaus Magdorf; Sara S Kilic; Yoshiyuki Minegishi; Shigeaki Nonoyama; Martyn A French; Sharon Choo; Joanne M Smart; Jane Peake; Melanie Wong; Paul Gray; Matthew C Cook; David A Fulcher; Jean-Laurent Casanova; Elissa K Deenick; Stuart G Tangye Journal: Blood Date: 2012-03-08 Impact factor: 22.113
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Authors: Stuart G Tangye; Julia Bier; Anthony Lau; Tina Nguyen; Gulbu Uzel; Elissa K Deenick Journal: J Clin Immunol Date: 2019-03-25 Impact factor: 8.317
Authors: Valter R Fonseca; Ana Agua-Doce; Ana Raquel Maceiras; Wim Pierson; Filipa Ribeiro; Vasco C Romão; Ana Rita Pires; Susana Lopes da Silva; João Eurico Fonseca; Ana E Sousa; Michelle A Linterman; Luis Graca Journal: Sci Immunol Date: 2017-08-11
Authors: Carole Le Coz; Bertram Bengsch; Caroline Khanna; Melissa Trofa; Takuya Ohtani; Brian E Nolan; Sarah E Henrickson; Michele P Lambert; Taylor Olmsted Kim; Jenny M Despotovic; Scott Feldman; Olajumoke O Fadugba; Patricia Takach; Melanie Ruffner; Soma Jyonouchi; Jennifer Heimall; Kathleen E Sullivan; E John Wherry; Neil Romberg Journal: J Allergy Clin Immunol Date: 2019-08-22 Impact factor: 10.793
Authors: Julia Bier; Geetha Rao; Kathryn Payne; Henry Brigden; Elise French; Simon J Pelham; Anthony Lau; Helen Lenthall; Emily S J Edwards; Joanne M Smart; Theresa S Cole; Sharon Choo; Avni Y Joshi; Roshini S Abraham; Michael O'Sullivan; Kaan Boztug; Isabelle Meyts; Paul E Gray; Lucinda J Berglund; Peter Hsu; Melanie Wong; Steven M Holland; Luigi D Notarangelo; Gulbu Uzel; Cindy S Ma; Robert Brink; Stuart G Tangye; Elissa K Deenick Journal: J Allergy Clin Immunol Date: 2019-02-06 Impact factor: 10.793
Authors: Bethany A Pillay; Danielle T Avery; Joanne M Smart; Theresa Cole; Sharon Choo; Damien Chan; Paul E Gray; Katie Frith; Richard Mitchell; Tri Giang Phan; Melanie Wong; Dianne E Campbell; Peter Hsu; John B Ziegler; Jane Peake; Frank Alvaro; Capucine Picard; Jacinta Bustamante; Benedicte Neven; Andrew J Cant; Gulbu Uzel; Peter D Arkwright; Jean-Laurent Casanova; Helen C Su; Alexandra F Freeman; Nirali Shah; Dennis D Hickstein; Stuart G Tangye; Cindy S Ma Journal: JCI Insight Date: 2019-04-25
Authors: Alexandra M Miggelbrink; Brent R Logan; Rebecca H Buckley; Roberta E Parrott; Christopher C Dvorak; Neena Kapoor; Hisham Abdel-Azim; Susan E Prockop; David Shyr; Hélène Decaluwe; Imelda C Hanson; Alfred Gillio; Blachy J Dávila Saldaña; Hermann Eibel; Gregory Hopkins; Jolan E Walter; Jennifer S Whangbo; Donald B Kohn; Jennifer M Puck; Morton J Cowan; Linda M Griffith; Elie Haddad; Richard J O'Reilly; Luigi D Notarangelo; Sung-Yun Pai Journal: Blood Date: 2018-05-04 Impact factor: 22.113