ICOS agonist vopratelimab modulates follicular helper T cells and improves B cell function in common variable immunodeficiency

• Published in: Clinical immunology (Orlando, Fla.) Vol. 264; p. 110217
• Main Authors: Sepahi, Ali, Ho, Hsi-en, Vyas, Prapti, Umiker, Benjamin, Kis-Toth, Katalin, Wiederschain, Dmitri, Radigan, Lin, Cunningham-Rundles, Charlotte
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2024
• Subjects: Common variable immune deficiency; Follicular helper T cells; ICOS; Increased Plasmablasts; Inducible T cell co-stimulator; Production of IL-10 and IL-4; Follicular helper T cells; Increased Plasmablasts; Inducible T cell co-stimulator; ICOS; Production of IL-10 and IL-4; Common variable immune deficiency
• ISSN: 1521-6616; 1521-7035; 1521-7035
• DOI: 10.1016/j.clim.2024.110217

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (TFH) play a central role in humoral immunity, we examined TFH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate TFH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased TFH17 and increased TFH1 subsets; this was associated with increased transitional B cells and decreased IgG+ B and IgD−IgM−CD27+ memory B cells. ICOS expression on CVID CD4+ T cells was also decreased. However, ICOS activation of CD4+ T cells by vopratelimab significantly increased total CVID TFH, TFH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG+ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of TFH modulation in restoring TFH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency. •Activation of the inducible T cell co-stimulator in common variable immune deficiency increased the numbers of follicular helper T cells.•ICOS activation enhanced CVID IL-10, and IL-4 production.•ICOS activation increased plasma cells, IgG+ B cells, and IgG1 secretion and IgA in a few subjects.