B Cell-Specific Deletion of CR6-Interacting Factor 1 Drives Lupus-like Autoimmunity by Activation of Interleukin-17, Interleukin-6, and Pathogenic Follicular Helper T Cells in a Mouse Model.

Abstract

CR6-interacting factor 1 (CRIF1) is a nuclear transcriptional regulator and a mitochondrial inner membrane protein; however, its functions in B lymphocytes have been poorly defined. This study was undertaken to investigate the effects of CRIF1 on B cell metabolic regulation, cell function, and autoimmune diseases. Using mice with B cell-specific deletion of CRIF1 (Crif1^ΔCD19 mice), we assessed the relevance of CRIF1 function for lupus disease parameters, including anti-double-stranded DNA (anti-dsDNA), cytokines, and kidney pathology. RNA sequencing was performed on B cells from Crif1^ΔCD19 mice. The phenotypic and metabolic changes in immune cells were evaluated in Crif1^ΔCD19 mice. Roquin^san/+ mice crossed with Crif1^ΔCD19 mice were monitored to assess the functionality of CRIF1-deficient B cells in lupus development. Crif1^ΔCD19 mice showed an autoimmune lupus-like phenotype, including high levels of autoantibodies to dsDNA and severe lupus nephritis with increased mesangial hypercellularity. While loss of CRIF1 in B cells showed impaired mitochondrial oxidative function, CRIF1-deficient B cells promoted the production of interleukin-17 (IL-17) and IL-6 and was more potent in helping T cells develop into follicular helper T cells. In a mouse model of autoimmune lupus, depletion of CRIF1 in B cells exacerbated lupus severity, and CRIF1 overexpression prevented lupus development in roquin^san/san mice. These results demonstrated that CRIF1 negatively correlates with disease severity and that overexpression of CRIF1 ameliorates disease development. Our findings suggest that CRIF1 is essential for preventing lupus development by maintaining B cell self tolerance.