Impaired ICOS signaling between Tfh and B cells distinguishes hospitalized from ambulatory CoViD-19 patients

Emerging evidence suggests that SARS-CoV-2 infections are characterized by systemic immune responses that appear to be dysregulated with more severe CoViD-19 disease. Lymphopenia and delayed antibody responses are commonly identified in CoViD-19 subjects, and recent reports have demonstrated abrogation of germinal centers in severe CoViD-19. This work assessed a potential mechanistic basis for impaired humoral responses, focusing on the T follicular helper (Tfh) and B cell interface that is critical for germinal center reactions. Here we demonstrated that Tfh activity is impaired in hospitalized relative to ambulatory CoViD-19 subjects, potentially due to decreased expression of the costimulatory molecule ICOS-L on B cells. Functional impairment manifested as a diminished ability to stimulated Tfh derived IFNγ and IL-21, the latter of which is critical for B cell proliferation and differentiation. Activation of Tfh cells by agonism of the ICOS receptor ex vivo by an agonistic antibody stimulated the generation of IFNγ/IL-21 double positive cells from hospitalized CoViD-19 subjects. This report establishes an immunological defect that differentiates ambulatory from hospitalized CoViD and suggests that agents that could restore impaired mechanisms at the Tfh–B cell interface may be of therapeutic value.