TY - JOUR
T1 - Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.
AU - Ma, Cindy S
AU - Wong, Natalie
AU - Rao, Geetha
AU - Avery, Danielle T
AU - Torpy, James
AU - Hambridge, Thomas
AU - Bustamante, Jacinta
AU - Okada, Satoshi
AU - Stoddard, Jennifer L
AU - Deenick, Elissa K
AU - Pelham, Simon J
AU - Payne, Kathryn
AU - Boisson-Dupuis, Stéphanie
AU - Puel, Anne
AU - Kobayashi, Masao
AU - Arkwright, Peter D
AU - Kilic, Sara Sebnem
AU - El Baghdadi, Jamila
AU - Nonoyama, Shigeaki
AU - Minegishi, Yoshiyuki
AU - Mahdaviani, Seyed Alireza
AU - Mansouri, Davood
AU - Bousfiha, Aziz
AU - Blincoe, Annaliesse K
AU - French, Martyn A
AU - Hsu, Peter
AU - Campbell, Dianne E
AU - Stormon, Michael O
AU - Wong, Melanie
AU - Adelstein, Stephen
AU - Smart, Joanne M
AU - Fulcher, David A
AU - Cook, Matthew C
AU - Phan, Tri Giang
AU - Stepensky, Polina
AU - Boztug, Kaan
AU - Kansu, Aydan
AU - İkincioğullari, Aydan
AU - Baumann, Ulrich
AU - Beier, Rita
AU - Roscioli, Tony
AU - Ziegler, John B
AU - Gray, Paul
AU - Picard, Capucine
AU - Grimbacher, Bodo
AU - Warnatz, Klaus
AU - Holland, Steven M
AU - Casanova, Jean-Laurent
AU - Uzel, Gulbu
AU - Tangye, Stuart G
PY - 2015/10
Y1 - 2015/10
N2 - 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.
AB - 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.
KW - Follicular helper T cells
KW - cytokine signaling
KW - humoral immunity
KW - primary immunodeficiencies
U2 - 10.1016/j.jaci.2015.05.036
DO - 10.1016/j.jaci.2015.05.036
M3 - Article
C2 - 26162572
SN - 1097-6825
VL - 136
JO - The Journal of allergy and clinical immunology
JF - The Journal of allergy and clinical immunology
IS - 4
ER -
