Amendt, T. | Search bioRxiv

bioRxiv2025

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.

immunology↗

bioRxiv2021

Antibodies control metabolism by regulating insulin homeostasis

Homeostasis of metabolism by hormone production is crucial to maintain physiological integrity and disbalance can cause severe metabolic disorders such as diabetes mellitus. Here, we show that antibodies recognizing insulin are key regulators of blood glucose and metabolism controlling insulin concentrations. In fact, antibody-deficient mice and immunodeficiency patients show sub-physiological blood glucose, which becomes normal after total IgG injection. We show that insulin-specific IgG antibodies found in the serum of wildtype mice or healthy individuals are responsible for this regulation. Interestingly, we identify two fractions of anti-insulin IgM which differ in their affinity to insulin. The low affinity IgM fraction (anti-insulin IgMlow) neutralizes insulin and leads to increased blood glucose while the high affinity IgM fraction (anti-insulin IgMhigh) protects insulin from neutralization by anti-insulin IgG thereby preventing blood glucose dysregulation. In contrast to anti-insulin IgMhigh, anti-insulin IgMlow binds to dsDNA suggesting that it is multi-specific. This multi-specificity mediates the formation of larger immune complexes containing insulin which results in increased uptake and degradation of insulin by macrophages in the presence of anti-insulin IgMlow as compared to anti-insulin IgMhigh. To demonstrate that high affinity anti-insulin IgM acts as protector of insulin and counteracts insulin neutralization by anti-insulin IgG, we expressed the variable regions of the same anti-insulin antibody as IgG or IgM. Strikingly, only the anti-insulin IgM regulated insulin function and prevented IgG-mediated neutralization of insulin and subsequent blood glucose dysregulation. Since anti-insulin IgMhigh is generated in the course of an immune response and affinity maturation, its protective role suggests that preventing autoimmune damage and maintaining physiological homeostasis requires adaptive tolerance mechanisms that generate protective IgM antibodies during memory responses.

immunology↗