CD22/Lyn-mediated suppression of trophoblast antigen-specific B cells underlies fetomaternal tolerance

Abstract

Abstract The placenta releases allogeneic trophoblast antigens into maternal circulation during pregnancy. Maternal antigen presenting cells present these antigens to T cells but fail to induce strong immunogenic responses, even in the presence of danger signals. While this observation illustrates the phenomenon of fetomaternal tolerance, its cellular and molecular basis remains largely unknown. By studying the pathways mediating adaptive immune responses to a surrogate trophoblast antigen in mice, we found that maternal B cells, and not regulatory T cells, directly underlie the impairments in CD4 T cell activation. Trophoblast-antigen specific B cells, rather than dendritic cells, are the main presenters of trophoblast antigen to CD4 T cells. The B cells are themselves profoundly suppressed, thus limiting their ability to activate cognate CD4 T cells. Mechanistically, B cell suppression occurs as the result of CD22/Lyn inhibitory signaling, likely induced by sialic acid residues that coat the trophoblast-derived antigen. These results not only identify maternal B cells as key players in fetomaternal tolerance but also provide a basis for further work on B cell responses during healthy and pathologic pregnancies. More broadly, these results suggest that exploiting antigen-intrinsic properties such as sialylation may provide new therapeutic ways to ignite or inhibit antigen-specific responses outside the context of pregnancy.