Expression of plasma cell alloantigen 1 defines layered development of B-1a B-cell subsets with distinct innate-like functions

Innate-like B-1a cells contribute significantly to circulating natural antibodies and mucosal immunity as well as to immunoregulation. Here we show that these classic functions of B-1a cells segregate between two unique subsets defined by expression of plasma cell alloantigen 1 (PC1), also known as ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). These subsets, designated B-1a.PC1lo and B-1a.PC1hi , differ significantly in IgH chain utilization. Adoptively transferred PC1lo cells secreted significantly more circulating natural IgM and intestinal IgA than PC1hi cells. In contrast, PC1hi cells produced more IL-10 than PC1lo cells when stimulated with LPS and phorbol 12-myristate 13-acetate (PMA). PC1hi cells were also more efficient than PC1lo cells in regulating Th1 cell differentiation, even though both B-1a subsets were comparably active in stimulating T-cell proliferation. Furthermore, PC1lo cells generated antigen-specific IgM responses to pneumococcal polysaccharide antigens, whereas PC1hi cells do not. We found that PC1lo cells develop from an early wave of B-1a progenitors in fetal life, whereas PC1hi cells are generated from a later wave after birth. We conclude that identification of B-1a.PC1lo and B-1a.PC1hi cells extends the concept of a layered immune system with important implications for developing effective vaccines and promoting the generation of immunoregulatory B cells.