Semaphorin3E is a novel regulator of germinal center responses in a mouse model of allergic asthma.

Abstract

Little is known about the role of semaphorin 3E (Sema3E) in B cell responses and immunoglobulin regulation. Our recent data indicate that Sema3e knockout mice have significantly higher serum levels of total and allergen-specific IgE in allergic asthma, suggesting Sema3E's crucial role in modulating the humoral response. We hypothesized that Sema3E may negatively regulate key T-dependent B cell processes, including germinal center (GC) responses and IgE production. To test this, Sema3e-/- and wild-type C57BL/6 mice underwent the acute house dust mite challenge protocol. We quantified GC B cells, T follicular helper (Tfh) cells, antibody-secreting cells (ASCs), IgE+ B cells, antibody isotypes (IgE, IgG1), and cytokines at baseline and upon allergen airway challenge. GC formation was blocked by intraperitoneal administration of anti-ICOS-L or rat IgG as an isotype control. At the steady state, Sema3e-/- mice had a significantly higher baseline number of GC B cells, Tfh cells, ASCs, and serum IgE compared with the wild-type counterparts. Upon house dust mite immunization, Sema3e-/- mice exhibited enhanced GC responses, IgE production, and B cell costimulatory molecules expression. Interestingly, Sema3E absence in mice led to an increase in the expression of ICOS on CD4+ T cells and disruption of ICOS/ICOS-L signaling, remarkably reducing the number of GC B cells, Tfh cells, IgE+ B cells, ASCs, serum levels of immunoglobulins, and lung inflammatory cells. Collectively, Sema3E may negatively regulate both enhanced GC responses and elevated IgE production at both steady state and postimmunization, highlighting its critical role in controlling humoral immunity and allergic inflammation.