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, St
ephanie 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 _Ikinciogullari, 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 and Stuart G. Tangye

Pediatric Respiratory Diseases Research Centre, NRITLD, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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.

Objectives: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects.

Materials and 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-offunction mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-g and programmed death 1. IFN-g 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-g 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, humoral immunity, primary immunodeficiencies, cytokine signaling

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J Allergy Clin Immunol 2015;136:993-1006.