title: Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.
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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Wong
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Geetha
authors.initials: G
authors.lastname: Rao
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Torpy
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hambridge
authors.affiliation: 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.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: Clinical Center, National Institutes of Health, Bethesda, Md.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stoddard
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia.
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Pelham
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Payne
authors.affiliation: 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.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: Department of Pediatric Immunology, Uludag University Medical Faculty, Görükle, Bursa, Turkey.
authors.forename: Sara Sebnem
authors.initials: SS
authors.lastname: Kilic
authors.affiliation: Genetics Unit, Military Hospital Mohamed V, Hay Riad, Rabat, Morocco.
authors.forename: Jamila
authors.initials: J
authors.lastname: El Baghdadi
authors.affiliation: Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.affiliation: Division of Molecular Medicine, Institute for Genome Research, University of Tokushima, Tokushima, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Minegishi
authors.affiliation: Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Seyed Alireza
authors.initials: SA
authors.lastname: Mahdaviani
authors.affiliation: Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Davood
authors.initials: D
authors.lastname: Mansouri
authors.affiliation: Clinical Immunology Unit, Pediatric Infectious Diseases Department, Averroes University Hospital, King Hasan II University, Casablanca, Morocco.
authors.forename: Aziz
authors.initials: A
authors.lastname: Bousfiha
authors.affiliation: Starship Children's Hospital, Auckland, New Zealand.
authors.forename: Annaliesse K
authors.initials: AK
authors.lastname: Blincoe
authors.affiliation: Department of Clinical Immunology, Royal Perth Hospital, Perth, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
authors.affiliation: Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hsu
authors.affiliation: Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Dianne E
authors.initials: DE
authors.lastname: Campbell
authors.affiliation: Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Stormon
authors.affiliation: Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.affiliation: Clinical Immunology, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Adelstein
authors.affiliation: Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Melbourne, Australia.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Smart
authors.affiliation: Department of Immunology, Westmead Hospital, University of Sydney, Westmead, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.affiliation: 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.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Melbourne, Australia.
authors.forename: Tri Giang
authors.initials: TG
authors.lastname: Phan
authors.affiliation: Pediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: 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.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.affiliation: Department of Pediatric Gastroenterology, Ankara University Medical School, Ankara, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: Kansu
authors.affiliation: Department of Pediatric Immunology and Allergy, Ankara University Medical School, Ankara, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: İkincioğullari
authors.affiliation: Paediatric Pulmonology, Allergy and Neonatology, Hanover Medical School, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.affiliation: Pediatric Haematology and Oncology, University Hospital Essen, Essen, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Beier
authors.affiliation: 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.
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.affiliation: Sydney Children's Hospital, Randwick, and School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Ziegler
authors.affiliation: Sydney Children's Hospital, Randwick, and School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gray
authors.affiliation: 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.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: 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.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: 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.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001402:B-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D056724:Immunity, Humoral / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D009154:Mutation / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: C556692:ICOS protein, human; C491731:IKBKG protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D018121:Receptors, Cytokine; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D023201:CD40 Ligand; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051550:I-kappa B Kinase
keywords: Follicular helper T cells; cytokine signaling; humoral immunity; primary immunodeficiencies