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

Hanson, A.; Cohen, H.; Wang, H.; Shekhar, N.; Shah, C.; Dhaneshwar, A.; Harvey, B. W.; Murray, R.; Harvey, C. J.

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 IFNg; 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 IFNg/IL-21 double positive cells from hospitalized CoViD-19 subjects. This report establishes an immunological defect that differentiates ambulatory from hospitalized CoViD-19 and suggests that agents that could restore impaired mechanisms at the Tfh-B cell interface may be of therapeutic value.