Browsing by Author "Payne, Kathryn"

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    Monogenic mutations differentially affect the quantity and quality of t follicular helper cells in patients with human primary immunodeficiencies
    (Mosby-elsevier, 2015-10-01) Ma, Cindy S.; Wong, Natalie; Rao, Geetha; Avery, Danielle T.; Torpy, James; Hambridge, Thomas; Bustamante, Jacinta; Okada, Satoshi; Stoddard, Jennifer L.; Deenick, Elissa K.; Pelham, Simon J.; Payne, Kathryn; Boisson-Dupuis, Stephanie; Puel, Anne; Kobayashi, Masao; Arkwright, Peter D.; 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 O.; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M.; Fulcher, David A.; Cook, Matthew C.; 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, Bodo; Warnatz, Klaus; Holland, Steven M.; Casanova, Jean-Laurent; Uzel, Gulbu; Tangye, Stuart G.; Kılıç, Sara Şebnem; KILIÇ GÜLTEKİN, SARA ŞEBNEM; Bursa Uludağ Üniversitesi/Tıp Fakültesi/İmmunoloji Anabilim Dalı.; 0000-0001-8571-2581
    Background: Follicular helper T (T-FH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. T-FH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T-FH 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-FH 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(FH)) 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(FH) cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cT(FH) cell differentiation toward a phenotype characterized by overexpression of IFN-gamma and programmed death 1. IFN-gamma inhibited cT(FH) 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 cT(FH) cells, highlighting the need to assess T-FH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-gamma functions in vivo to restrain T-FH cell-induced B-cell differentiation. These findings shed new light on T-FH 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.
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    Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4(+) T cells into distinct effector subsets
    (Rockefeller University Press, 2016-07-25) Ma, Cindy S.; Wong, Natalie; Rao, Geetha; Nguyen, Akira; Avery, Danielle T.; Payne, Kathryn; Torpy, James; O'Young, Patrick; Deenick, Elissa; Bustamante, Jacinta; Puel, Anne; Okada, Satoshi; Kobayashi, Masao; Martinez-Barricarte, Ruben; Elliott, Michael; El Baghdadi, Jamila; Minegishi, Yoshiyuki; Bousfiha, Aziz; Robertson, Nic; Hambleton, Sophie; Arkwright, Peter D.; French, Martyn; Blincoe, Annaliesse K.; Hsu, Peter; Campbell, Dianne E.; Stormon, Michael O.; Wong, Melanie; Adelstein, Stephen; Fulcher, David A.; Cook, Matthew C.; Stepensky, Polina; Boztuğ, Kaan; Beier, Rita; İkincioğulları, Aydan; Ziegler, John B.; Gray, Paul; Picard, Capucine; Boisson-Dupuis, Stephanie; Tri Giang, Phan; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M.; Uzel, Gülbü; Casanova, Jean-Laurent; Tangye, Stuart G.; Kılıç, Sara Şebnem; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; AAH-1658-2021; 34975059200
    Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12R beta 1/TYK2 and IFN-gamma R/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12R beta 1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.