Dissecting the role of galectin-3, IFN-γ and microbiota in germinal center B cell fate decisions

MONTES CL; RAMELLO MC; AMEZCUA VESELY MC; GRUPPI A; CAMPETELLA O; MUCCI J; FIOCCA VERNENGO F; ACOSTA RODRIGUEZ EV; TOSELLO BOARI J; ALMADA L; BECCARIA CG

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Germinal Centers (GC) are unique structures where high affinityantibodies and memory B cells are generated. With the aim of ensurefast selection of rapidly evolving clones in GCs, follicular dendriticcells, GC B cells and T cells engage in multiple interactions.So far, only co-stimulatory or inhibitory membrane immune receptor/ligand pairs and cytokines have been investigated and are knownto be involved in this process. However, there is a pressing need tounderstand other factors that regulate GCs in order to optimize andcontrol humoral responses following vaccination, antibody-mediatedautoimmune diseases, and GC B cell-derived malignancies. Here,we report a novel effector function by which Galectin-3 (Gal-3), aβ-galactoside binding protein, is critically involved in the developmentof GCs. Gal-3 KO mice exhibit high frequency of spontaneousGC (sGC) B cells and T follicular helper (Tfh) cells that correlatedwith hypergammaglobulinemia, high amounts of IFN-γ in serumand lupus-like autoimmune manifestations. We found that the mainsource of IFN-γ in Gal-3 KO mice were CD4+ T cells (including Tfh),since there are no significant differences between IFN-γ-producingCD8 T, NK, NKT and DCs cells between groups. IFN-γ blockade inGal-3 KO mice prevents the autoimmune condition, demonstratingthat IFN-γ overproduction sustain lupus-like disease. We were alsowondering whether specific microbiota in Gal-3 mice could influencethe induction of sGCs. Microbiota modulation by antibiotic treatmentcould not prevent sGCs induction in Gal-3 KO mice and, interestingly,these mice did not modify the generation of GCs in Peyer?spatches after treatment, unlike the WT mice which showed a deepreduction of them. Finally, using chimeric mice with B cell-specificdeficiency of Gal-3, we reveal that intrinsic Gal-3 signaling in B cellscontrol sGC formation. Together, our data provide the first evidencethat Gal-3 acts directly on B cells regulating GCs responses viaIFN-γ.