β‐adrenoceptor blockade affects the germinal center B cell response to seasonal quadrivalent inactivated influenza vaccine (QIV) in mice

Abstract

The study was undertaken considering importance of antibody response for influenza vaccine efficacy and data indicating that β2‐adrenoceptor stimulation may affect antibody generation. To elucidate influence of β‐adrenoceptor‐mediated signaling on antibody response to QIV, serum titers of QIV‐specific IgG and draining lymph node and splenic germinal center (GC) reaction to QIV were examined in BALB/c mice treated with propranolol, non‐selective β‐adrenoceptor blocker, or vehicle (controls) daily, beginning two days before immunization. Four weeks after immunization IgG antibody titer was decreased in propranolol‐treated mice. This correlated with lower frequency of GC B cells in lymphoid organs of propranolol‐treated mice, and their diminished proliferation upon restimulation with QIV antigens in culture. Consistently, Tfh/Tfr cell ratio was shifted towards the latter in propranolol‐treated mice. This correlated with lower frequency of QIV‐specific CD4+ cells that produce IL‐21, the key regulator of GC reaction, in lymphoid organs of propranolol‐ treated mice, as suggested by in vitro recall test. Additionally, propranolol treatment shifted IgG1/IgG2a antibody ratio towards IgG1 antibody (contributing mainly to the virus clearance). This was consistent with the shift in IFN‐γ/IL‐4 ratio to the site of IL‐4 in QIV‐stimulated splenocyte cultures from propranolol‐treated mice compared with controls. Thus, the study suggests that chronic administration of propranolol, drug widely used for cardiovascular pathology, and recently repurposed for several other pathologies, including cancer, rheumatoid arthritis, and anxiety may impair efficacy of QIV by affecting CD4+ T‐cell cytokine secretory profile and thereby overall efficacy of Tfh help to B cells, and its influence on IgG subclass switching pattern.