Critical Role Of Foxo1 In Germinal Center B Cells

Germinal centers(GCs)reaction is a T cells-dependent process in which activated B-cells mature to produce high-affinity antibodies and differentiate into memory B-cells.Foxo1 is essential for B-cells development and lymphopoiesis by regulating several critical genes involved in immunoglobulin(Ig)gene rearrangement.However,the role of Foxo1 in antigen-driven B-cells activation and functional differentiation has not been established.We examined the antibody response in GC B cells-specific Foxol conditional knockout(CKO)mice,which were generated using Cyl-Cre-mediated gene deletion.We found that both primary and memory antibody responses in Foxol GC B-cells CKO mice were severely impaired.In addition,class-switch recombination(CSR)and Ig somatic hypermutation(SHM)were defective in Foxol-/-GC B-cells.The clonotypes of responding B-cells were also significantly altered in the mutant mice.Deletion of Foxol in GC B-cells led to obviously reduced expression of activation-induced cytidine deaminase(AID),which caused AID involved CSR and SHM impaired severely.We have further investigated the effect of diminished Foxo1 expression on the pathogenesis of autoimmune diseases.Remarkably,this dysregulated GC response in Foxol-deficient mice led to resistance to disease induction in a collagen-induced arthritis(CIA)model,demonstrating a critical role of Foxol in regulating autoimmune response.