DOCK8 gene mutation alters cell subsets, BCR signaling, and cell metabolism in B cells.

Abstract

DOCK8 deficiency has been shown to affect the migration, function, and survival of immune cells in innate and adaptive immune responses. The immunological mechanisms underlying autosomal recessive (AR) hyper-IgE syndrome (AR-HIES) caused by DOCK8 mutations remain unclear, leading to a lack of specific therapeutic options. In this study, we used CRISPR/Cas9 technology to develop a mouse model with a specific DOCK8 point mutation in exon 45 (c.5846C>A), which is observed in patients with AR-HIES. We then investigated the effect of this mutation on B cell development, cell metabolism, and function in a mouse model with Dock8 gene mutation. The results demonstrated that Dock8 gene mutation inhibited splenic MZ and GC B cell development and crippled BCR signaling. In addition, it resulted in enhanced glycolysis in B cells. Mechanistically, the reduced BCR signaling was related to decreased B cell spreading, BCR clustering, and signalosomes, mediated by inhibited activation of WASP. Furthermore, the DOCK8 mutation led to increased expression of c-Myc in B cells, which plays an important role in glycolysis. As such, GC B cells' formation and immune responses were disturbed in LCMV-infected mice. These findings will provide new insights into the immunological pathogenesis of primary immunodeficiency disorder caused by DOCK8 mutation.