Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies

Cindy S Ma; Natalie Wong; Geetha Rao; Danielle T Avery; James Torpy; Thomas Hambridge; Jacinta Bustamante; Satoshi Okada; Jennifer L Stoddard; Elissa K Deenick; Simon J Pelham; Kathryn Payne; Stéphanie Boisson-Dupuis; Anne Puel; Masao Kobayashi; Peter D Arkwright; Sara Sebnem Kilic; Jamila El Baghdadi; Shigeaki Nonoyama; Yoshiyuki Minegishi; Seyed Alireza Mahdaviani; Davood Mansouri; Aziz Bousfiha; Annaliesse K Blincoe; Martyn A French; Peter Hsu; Dianne E Campbell; Michael O Stormon; Melanie Wong; Stephen Adelstein; Joanne M Smart; David A Fulcher; Matthew C Cook; Tri Giang Phan; Polina Stepensky; Kaan Boztug; Aydan Kansu; Aydan İkincioğullari; Ulrich Baumann; Rita Beier; Tony Roscioli; John B Ziegler; Paul Gray; Capucine Picard; Bodo Grimbacher; Klaus Warnatz; Steven M Holland; Jean-Laurent Casanova; Gulbu Uzel; Stuart G Tangye

doi:10.1016/j.jaci.2015.05.036

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies

J Allergy Clin Immunol. 2015 Oct;136(4):993-1006.e1. doi: 10.1016/j.jaci.2015.05.036. Epub 2015 Jul 7.

Authors

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

Affiliations

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.

Keywords: Follicular helper T cells; cytokine signaling; humoral immunity; primary immunodeficiencies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Agammaglobulinaemia Tyrosine Kinase
B-Lymphocytes / immunology
CD40 Ligand / genetics
Cell Differentiation / genetics
Cell Proliferation / genetics
Cells, Cultured
Humans
I-kappa B Kinase / genetics
Immunity, Humoral / genetics
Immunologic Deficiency Syndromes / genetics
Immunologic Deficiency Syndromes / immunology*
Immunologic Memory
Inducible T-Cell Co-Stimulator Protein / genetics
Interferon-gamma / genetics
Interferon-gamma / metabolism
Lymphocyte Activation
Mutation / genetics
Protein-Tyrosine Kinases / genetics
Receptors, Cytokine / genetics
STAT1 Transcription Factor / genetics
STAT3 Transcription Factor / genetics
Signal Transduction / genetics
Signal Transduction / immunology
T-Lymphocyte Subsets / immunology*
T-Lymphocytes, Helper-Inducer / immunology*

Substances

ICOS protein, human
IKBKG protein, human
Inducible T-Cell Co-Stimulator Protein
Receptors, Cytokine
STAT1 Transcription Factor
STAT1 protein, human
STAT3 Transcription Factor
STAT3 protein, human
CD40 Ligand
Interferon-gamma
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human
I-kappa B Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding