B cells require histamine receptor signals for efficient antibody responses

Mast cells and basophils release histamine following antigen-specific activation via IgE and underpin allergic responses. The functions of histamine are regulated through four receptors (H1R-H4R) that are differentially expressed on both hematopoietic and non-hematopoietic cell types. Increasing evidence supports innate mast cell activation participating in the priming phase of allergen responses through histamine-mediated regulation of CD4+ T cells and dendritic cells. However, regulation of B cells by histamine remains unknown and so we sought to address this. While most immune cells express H4R, our data demonstrates that both murine and human B cells exclusively express H1R and H2R; expression levels differed between specific B cell subsets and upon activation, but there was no evidence for expression of H4R. Mice lacking H2R produced significantly less antigen-specific IgE upon immunization, whereas mice lacking H1R were unaffected. Deletion of both receptors in mice (H1R/H2R DKO) led to profound diminishment of most antibody isotypes, with an absence of antigen-specific antibodies. This was not due to T cell-intrinsic influences since antigen-stimulated production of T-cell associated cytokines was unaltered. B cell subsets were normal in H1R/H2R DKO mice, implicating a functional impairment rather than developmental. Mechanistically defining this, reconstitution of Rag1 knockout mice with WT T cells and H1R/H2R DKO B220+ B cells demonstrated impaired antibody production while H1R/H2R DKO T cells and WT B cells was competent. Additionally, in vitro stimulation of B220+ B cells from H1R/H2R DKO mice led to significantly less antibodies than WT. Collectively, our data defines a novel requirement for histamine in regulating B cell antibody responses.