Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 4; pp. 993 - 1006.e1
• Main Authors: Ma, Cindy S., PhD, Wong, Natalie, BSc Hons, Rao, Geetha, MSc, Avery, Danielle T., BApplSci, Torpy, James, MPhil, Hambridge, Thomas, BSc Hons, Bustamante, Jacinta, MD, PhD, Okada, Satoshi, MD, PhD, Stoddard, Jennifer L., BS, Deenick, Elissa K., PhD, Pelham, Simon J., MSc, Payne, Kathryn, BSc Hons, Boisson-Dupuis, Stéphanie, PhD, Puel, Anne, PhD, Kobayashi, Masao, MD, PhD, Arkwright, Peter D., FRCPCH, DPhil, Kilic, Sara Sebnem, MD, El Baghdadi, Jamila, PhD, Nonoyama, Shigeaki, MD, PhD, Minegishi, Yoshiyuki, MD, PhD, Mahdaviani, Seyed Alireza, MD, Mansouri, Davood, MD, Bousfiha, Aziz, MD, Blincoe, Annaliesse K., BHB, MBChB, French, Martyn A., MB ChB, MD, FRACP, FRCPath, FRCP, Hsu, Peter, FRACP, PhD, Campbell, Dianne E., FRACP, PhD, Stormon, Michael O., MBBS, FRACP, Wong, Melanie, MBBS, PhD, FRACP, FRCPA, Adelstein, Stephen, MBBCh, PhD, FRACP, FRCPA, Smart, Joanne M., MBBS, FRACP, Fulcher, David A., MBBS, PhD, FRACP, FRCPA, Cook, Matthew C., MBBS, PhD, FRACP, FRCPA, Phan, Tri Giang, MBBS, PhD, FRACP, FRCPA, Stepensky, Polina, MD, Boztug, Kaan, MD, Kansu, Aydan, MD, İkincioğullari, Aydan, MD, Baumann, Ulrich, MD, Beier, Rita, MD, Roscioli, Tony, FRACP, PhD, Ziegler, John B., MD, FRACP, Gray, Paul, FRACP, Picard, Capucine, MD, PhD, Grimbacher, Bodo, MD, Warnatz, Klaus, MD, PhD, Holland, Steven M., MD, Casanova, Jean-Laurent, MD, PhD, Uzel, Gulbu, MD, Tangye, Stuart G., PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015; Elsevier Limited
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Allergy and Immunology; Antigens; B-Lymphocytes - immunology; CD40 Ligand - genetics; Cell Differentiation - genetics; Cell Proliferation - genetics; Cells, Cultured; cytokine signaling; Cytokines; Follicular helper T cells; Gene expression; HIV; Human immunodeficiency virus; Humans; humoral immunity; I-kappa B Kinase - genetics; Immunity, Humoral - genetics; Immunoglobulins; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Memory; Inducible T-Cell Co-Stimulator Protein - genetics; Infections; Interferon-gamma - genetics; Interferon-gamma - metabolism; Lymphocyte Activation; Lymphocytes; Mutation - genetics; primary immunodeficiencies; Protein-Tyrosine Kinases - genetics; Receptors, Cytokine - genetics; Signal Transduction - genetics; Signal Transduction - immunology; STAT1 Transcription Factor - genetics; STAT3 Transcription Factor - genetics; T cell receptors; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Helper-Inducer - immunology; Signal transducer and activator of transcription; humoral immunity; Follicular regulatory T; Bcl-6; Loss of function; DN; DP; T-dependent; Programmed death 1; Germinal center; Follicular helper T; Regulatory T; B-cell lymphoma 6; Gain of function; GC; IL-21R; Circulating follicular helper T; GOF; LOF; IL-21 receptor; Treg; cT FH; Double-negative; IL-12 receptor; T FH; Follicular helper T cells; PID; Primary immunodeficiency; Double-positive; TD; IL-12R; STAT; primary immunodeficiencies; IL-10 receptor; cytokine signaling; IL-10R; PD-1; T FR; TFR; TFH; cTFH
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.05.036

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.