Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies
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Ma, Cindy; Wong, Natalie; Rao, Geetha; Avery, Danielle T; Torpy, James; Hambridge, Thomas; Bustamante, Jacinta; Okada , Satoshi; Stoddard, Jennifer L; Deenick, Elissa; Pelham, Simon J.; Payne, Kathryn; Boisson-Dupuis, Stephanie; Puel, Anne; Kobayashi, Masao; Arkwright, Peter D; Kilic, Sara Sebnem; El Baghdadi, Jamila; Nonoyama, Shigeaki; Minegishi, Yoshiyuki; Mahdaviani, Seyed Alireza; Mansouri, Davood; Bousfiha, Aziz; Blincoe, Annaliesse K.; French, Martyn A.; Hsu, Peter; Campbell, Dianne E.; Stormon, Michael; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M.; Fulcher, David; Cook, Matthew; Phan, Tri Giang; Stepensky, Polina; Boztug, Kaan; Kansu, Aydan; Ikinciogullari, Aydan; Baumann, Ulrich; Beier, Rita; Roscioli, Tony; Ziegler, John B; Gray, Paul; Picard, Capucine; Grimbacher, B.; Warnatz, Klaus; Holland, Steven M.; Casanova, Jean-Laurent; Uzel, G; Tangye, Stuart
Description
Background: Follicular helper T (T<inf>FH</inf>) cells underpin T cell-dependent humoral immunity and the success of most vaccines. T<inf>FH</inf> cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T<inf>FH</inf> cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective: We sought...[Show more]
dc.contributor.author | Ma, Cindy | |
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dc.contributor.author | Wong, Natalie | |
dc.contributor.author | Rao, Geetha | |
dc.contributor.author | Avery, Danielle T | |
dc.contributor.author | Torpy, James | |
dc.contributor.author | Hambridge, Thomas | |
dc.contributor.author | Bustamante, Jacinta | |
dc.contributor.author | Okada , Satoshi | |
dc.contributor.author | Stoddard, Jennifer L | |
dc.contributor.author | Deenick, Elissa | |
dc.contributor.author | Pelham, Simon J. | |
dc.contributor.author | Payne, Kathryn | |
dc.contributor.author | Boisson-Dupuis, Stephanie | |
dc.contributor.author | Puel, Anne | |
dc.contributor.author | Kobayashi, Masao | |
dc.contributor.author | Arkwright, Peter D | |
dc.contributor.author | Kilic, Sara Sebnem | |
dc.contributor.author | El Baghdadi, Jamila | |
dc.contributor.author | Nonoyama, Shigeaki | |
dc.contributor.author | Minegishi, Yoshiyuki | |
dc.contributor.author | Mahdaviani, Seyed Alireza | |
dc.contributor.author | Mansouri, Davood | |
dc.contributor.author | Bousfiha, Aziz | |
dc.contributor.author | Blincoe, Annaliesse K. | |
dc.contributor.author | French, Martyn A. | |
dc.contributor.author | Hsu, Peter | |
dc.contributor.author | Campbell, Dianne E. | |
dc.contributor.author | Stormon, Michael | |
dc.contributor.author | Wong, Melanie | |
dc.contributor.author | Adelstein, Stephen | |
dc.contributor.author | Smart, Joanne M. | |
dc.contributor.author | Fulcher, David | |
dc.contributor.author | Cook, Matthew | |
dc.contributor.author | Phan, Tri Giang | |
dc.contributor.author | Stepensky, Polina | |
dc.contributor.author | Boztug, Kaan | |
dc.contributor.author | Kansu, Aydan | |
dc.contributor.author | Ikinciogullari, Aydan | |
dc.contributor.author | Baumann, Ulrich | |
dc.contributor.author | Beier, Rita | |
dc.contributor.author | Roscioli, Tony | |
dc.contributor.author | Ziegler, John B | |
dc.contributor.author | Gray, Paul | |
dc.contributor.author | Picard, Capucine | |
dc.contributor.author | Grimbacher, B. | |
dc.contributor.author | Warnatz, Klaus | |
dc.contributor.author | Holland, Steven M. | |
dc.contributor.author | Casanova, Jean-Laurent | |
dc.contributor.author | Uzel, G | |
dc.contributor.author | Tangye, Stuart | |
dc.date.accessioned | 2016-02-24T22:40:35Z | |
dc.identifier.issn | 0091-6749 | |
dc.identifier.uri | http://hdl.handle.net/1885/98372 | |
dc.description.abstract | Background: Follicular helper T (T<inf>FH</inf>) cells underpin T cell-dependent humoral immunity and the success of most vaccines. T<inf>FH</inf> cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T<inf>FH</inf> 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 T<inf>FH</inf> 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 (cT<inf>FH</inf>) 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 cT<inf>FH</inf> cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cT<inf>FH</inf> cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cT<inf>FH</inf> cell function invitro and invivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Conclusion: Specific mutations affect the quantity and quality of cT<inf>FH</inf> cells, highlighting the need to assess T<inf>FH</inf> cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions invivo to restrain T<inf>FH</inf> cell-induced B-cell differentiation. These findings shed new light on T<inf>FH</inf> 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. | |
dc.publisher | Mosby Inc | |
dc.source | Journal of Allergy and Clinical Immunology | |
dc.title | Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 136 | |
dc.date.issued | 2015 | |
local.identifier.absfor | 110700 - IMMUNOLOGY | |
local.identifier.ariespublication | a383154xPUB2789 | |
local.type.status | Published Version | |
local.contributor.affiliation | Ma, Cindy S., Garvan Institute of Medical Research | |
local.contributor.affiliation | Wong, Natalie, Garvan Institute of Medical Research | |
local.contributor.affiliation | Rao, Geetha, Garvan Institute of Medical Research | |
local.contributor.affiliation | Avery, Danielle T, Garvan Institute of Medical Research | |
local.contributor.affiliation | Torpy, James, Garvan Institute of Medical Research | |
local.contributor.affiliation | Hambridge, Thomas, Garvan Institute of Medical Research | |
local.contributor.affiliation | Bustamante, Jacinta, Necker Medical School, University of Paris Descartes | |
local.contributor.affiliation | Okada , Satoshi, Hiroshima University | |
local.contributor.affiliation | Stoddard, Jennifer L., National Institutes of Health | |
local.contributor.affiliation | Deenick, Elissa, Garvan Institute of Medical Research | |
local.contributor.affiliation | Pelham, Simon J., University of New South Wales | |
local.contributor.affiliation | Payne, Kathryn, Garvan Institute of Medical Research | |
local.contributor.affiliation | Boisson-Dupuis, Stephanie, Necker Medical School, University of Paris Descartes | |
local.contributor.affiliation | Puel, Anne, University Paris | |
local.contributor.affiliation | Kobayashi, Masao, Hiroshima University Graduate School of Biomedical and Health Sciences | |
local.contributor.affiliation | Arkwright, Peter D, University of Manchester | |
local.contributor.affiliation | Kilic, Sara Sebnem, Uludag University Medical Faculty | |
local.contributor.affiliation | El Baghdadi, Jamila, Uludag University Medical Faculty | |
local.contributor.affiliation | Nonoyama, Shigeaki, National Defense Medical College | |
local.contributor.affiliation | Minegishi, Yoshiyuki, University of Tokushima | |
local.contributor.affiliation | Mahdaviani, Seyed Alireza, Shahid Beheshti University of Medical Sciences | |
local.contributor.affiliation | Mansouri, Davood, Shahid Beheshti University of Medical Sciences | |
local.contributor.affiliation | Bousfiha, Aziz, King Hasan II University | |
local.contributor.affiliation | Blincoe, Annaliesse K., Starship Children’s Hospital | |
local.contributor.affiliation | French, Martyn A., University of Western Australia | |
local.contributor.affiliation | Hsu, Peter, Children's Hospital Westmead | |
local.contributor.affiliation | Campbell, Dianne E., Children's Hospital Westmead | |
local.contributor.affiliation | Stormon, Michael, Children's Hospital Westmead | |
local.contributor.affiliation | Wong, Melanie, Childrens' Hospital at Westmead | |
local.contributor.affiliation | Adelstein, Stephen, Royal Prince Alfred Hospital | |
local.contributor.affiliation | Smart, Joanne M., Royall Children's Hospital | |
local.contributor.affiliation | Fulcher , David A. , Westmead Hospital, Sydney | |
local.contributor.affiliation | Cook, Matthew, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Phan, Tri Giang , University of New South Wales | |
local.contributor.affiliation | Stepensky, Polina, Hadassah Hebrew University | |
local.contributor.affiliation | Boztug, Kaan, Austrian Academy of Science | |
local.contributor.affiliation | Kansu, Aydan, Ankara University Medical School | |
local.contributor.affiliation | Ikinciogullari, Aydan, Ankara University Medical School | |
local.contributor.affiliation | Baumann, Ulrich, Hanover Medical School | |
local.contributor.affiliation | Beier, Rita, University Hospital Essen | |
local.contributor.affiliation | Roscioli, Tony, Sydney Children's Hospital | |
local.contributor.affiliation | Ziegler, John B, Sydney Children's Hospital | |
local.contributor.affiliation | Gray, Paul, University of New South Wales | |
local.contributor.affiliation | Picard, Capucine, Necker Hospital | |
local.contributor.affiliation | Grimbacher, B., University of Freiburg | |
local.contributor.affiliation | Warnatz, Klaus, University of Freiburg | |
local.contributor.affiliation | Holland, Steven M., National Institutes of Health | |
local.contributor.affiliation | Casanova, Jean-Laurent, Paris Descartes University | |
local.contributor.affiliation | Uzel, G, National Institutes of Health | |
local.contributor.affiliation | Tangye, Stuart, Garvan Institute of Medical Research | |
local.description.embargo | 2037-12-31 | |
local.bibliographicCitation.issue | 4 | |
local.bibliographicCitation.startpage | 993 | |
local.bibliographicCitation.lastpage | 1006 | |
local.identifier.doi | 10.1016/j.jaci.2015.05.036 | |
dc.date.updated | 2016-02-24T08:06:46Z | |
local.identifier.scopusID | 2-s2.0-84936068384 | |
Collections | ANU Research Publications |
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