PD-L2 Regulates Natural Antibody and IL-10 Secretion by B-1 cells

B-1 cells are innate-like lymphocytes that play a critical role in homeostasis by secreting natural antibodies, typically IgM, and immunosuppressive molecules such as IL-10. However, the regulation of these processes in B-1 cells remains poorly understood. Here, we demonstrate that PD-L2, a surface receptor expressed by all B-1 cells, regulates B-1 cell effector functions. We show that in contrast to the Mus musculus castaneus mouse and other mammals, commonly used laboratory mouse strains have a mutation resulting in a premature stop codon and hence a truncated PD-L2 lacking an intracellular domain. By reverting this mutation, we generated mice expressing full-length PD-L2 containing an intracellular domain. Using these, we found that PD-L2 signaling via the intracellular domain increases IL-10 secretion and decreases natural IgM secretion by B-1 cells, potentially due to reduced expression of plasma cell identity genes Blimp-1 and IRF4. These findings indicate direct cell-cell interaction-dependent regulation of B-1 cell effector functions mediated by PD-L2 signaling into B-1 cells.