IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans

• Published in: Blood Vol. 121; no. 17; pp. 3375 - 3385
• Main Authors: Schmitt, Nathalie, Bustamante, Jacinta, Bourdery, Laure, Bentebibel, Salah Eddine, Boisson-Dupuis, Stephanie, Hamlin, Fran, Tran, Mau V., Blankenship, Derek, Pascual, Virginia, Savino, Daniel A., Banchereau, Jacques, Casanova, Jean-Laurent, Ueno, Hideki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.04.2013; American Society of Hematology
• Subjects: Adolescent; Adult; Blotting, Western; Case-Control Studies; Child; Child, Preschool; Flow Cytometry; Fluorescent Antibody Technique; Germinal Center - immunology; Germinal Center - metabolism; Germinal Center - pathology; Humans; Immunobiology; Immunoenzyme Techniques; Immunologic Memory - immunology; Interleukin-12 - immunology; Interleukin-12 - metabolism; Interleukin-23 - immunology; Interleukin-23 - metabolism; Lymph Nodes - immunology; Lymph Nodes - metabolism; Palatine Tonsil - immunology; Palatine Tonsil - metabolism; Phosphorylation; Plasma Cells - immunology; Plasma Cells - metabolism; Receptors, Interleukin-12 - deficiency; Receptors, Interleukin-12 - physiology; STAT4 Transcription Factor - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-08-448902

Antibody responses represent a key immune protection mechanism. T follicular helper (Tfh) cells are the major CD4+ T-cell subset that provides help to B cells to generate an antibody response. Tfh cells together with B cells form germinal centers (GCs), the site where high-affinity B cells are selected and differentiate into either memory B cells or long-lived plasma cells. We show here that interleukin-12 receptor β1 (IL-12Rβ1)–mediated signaling is important for in vivo Tfh response in humans. Although not prone to B cell-deficient–associated infections, subjects lacking functional IL-12Rβ1, a receptor for IL-12 and IL-23, displayed substantially less circulating memory Tfh and memory B cells than control subjects. GC formation in lymph nodes was also impaired in IL-12Rβ1–deficient subjects. Consistently, the avidity of tetanus toxoid–specific serum antibodies was substantially lower in these subjects than in age-matched controls. Tfh cells in tonsils from control individuals displayed the active form of signal transducer and activator of transcription 4 (STAT4), demonstrating that IL-12 is also acting on Tfh cells in GCs. Thus, our study shows that the IL-12–STAT4 axis is associated with the development and the functions of Tfh cells in vivo in humans. •IL-12Rβ1–deficient subjects displayed substantially less circulating memory Tfh and memory B cells than control subjects.•The IL-12–STAT4 axis is associated with the development and functions of Tfh cells in vivo in humans.