Galectin-3 deficiency drives lupus-like disease by promoting spontaneous germinal centers formation via IFN-γ

GRUPPI, ADRIANA; CAMPETELLA, OSCAR; TOSELLO BOARI, JIMENA; FIOCCA VERNENGO, FACUNDO; MONTES, CAROLINA LUCÍA; MUCCI, JUAN; ACOSTA RODRÍGUEZ, EVA VIRGINIA; RAMELLO, MARÍA CECILIA; GOROSITO SERRÁN, MELISA; BECCARIA, CRISTIAN GABRIEL; AMEZCUA VESELY, MARÍA CAROLINA

Milano

Congreso; 19th International Conference on Lymphatic Tissues and Germinal Centres in Immune Reactions (GCC); 2017

The FIRC Institute of Molecular Oncology Foundation

Germinal centers (GC) are important sites where the production of high-affinity and long-lived antibodies (Abs) is determined. A fine-tuned balance between initiation and resolution of the GC response is required for the prevention of autoimmune conditions. Therefore, a comprehensive understanding of the factors that positively or negatively regulate GC activity is vital. Here, we report a novel effector function by which Galectin-3 (Gal-3), a β-galactoside binding protein, is critically involved in the development of GC. Gal-3 KO mice exhibit a high frequency of GC B cells and T follicular helper (Tfh) cells that correlated with increased percentage of Ab-secreting cells and high concentrations of IgM, IgG2c, IgG3 and IFN-γ in serum. We found that the main source of IFN-γ in Gal-3 KO mice were CD4+ T cells (including Tfh cells), since there are no differences between IFN-γ-producing CD8+ T, NK, NKT and DCs cells between WT and Gal-3 KO mice. Compatible with the marked increase in spontaneous GC response, Gal-3 KO mice develop a lupus-like disease, characterized by kidney infiltration and antinuclear Ab secretion. IFN-γ blockade in Gal-3 KO mice reduced GC formation, Ab class-switching, autoantibodies production and renal pathology, demonstrating that IFN-γ overproduction sustain lupus-like disease. It is also important to note that our study evidenced no differences in frequencies and numbers of Tregs, and no changes were exhibited in the expression of inhibitory molecules in Tregs from WT and Gal-3 KO mice. Finally, using chimeric mice with B cell-specific deficiency of Gal-3, we further demonstrate that intrinsic Gal-3 signaling in B cells control spontaneous GC formation. Together, our data provide the first evidence that Gal-3 acts directly on B cells regulating GCs responses via IFN-γ.