Foxo1 is essential for germinal center B cell functions and the development of collagen-induced arthritis (101.15)

Abstract

Abstract Foxo1 has been shown to be critical for B-cell lymphopoiesis by regulating several genes involved in immunoglobulin (Ig) rearrangement. However, the role of Foxo1 in germinal center (GC) B cell functions remains unclear. Unlike being downregulated in activated B cells, Foxo1 expression is elevated in GC B cells, suggesting a distinctive regulatory role. In Foxo1 GC B-cell conditional knockout (CKO) mice, both primary and memory antibody responses are severely impaired after immunization with T-dependent antigen NP-CGG. The numbers of NP-specific IgG1-secreting B-cells, as well as the NP-specific IgG1 antibody titer in the serum, are dramatically reduced in the mutant mice. The results indicate an inability to undergo Ig class-switch recombination (CSR) in Foxo1-deficient GC B cells, possibly due to the abolished expression of activation-induced cytidine deaminase. In addition, analysis of mutation rate of Ig genes in the NP-specific B cells reveals that Ig somatic hypermutation (SHM) is impaired in the Foxo1-deficient GC B cells. The clonotypes of B cells responding to NP are also altered in the mutant mice. Remarkably, using collagen-induced arthritis model, we have found that Foxo1 GC B-cell CKO mice are resistant to arthritis induction. Taken together, our data indicate that Foxo1 is essential for normal antibody responses, CSR and SHM of GC B cells. The absence of Foxo1 in GC B cells prevents the development of autoimmune arthritis.