NLRX1 deficiency promotes follicular helper T cell expansion and autoimmunity 4446

Abstract Description NLRX1 is a member of the NLR family and mitochondrial pattern recognition receptor that functions as a negative regulator of the RIG-I, NF-κB signaling, and the NLRP3 inflammasome activation. However, little is known about the interface of NLRX1 with the differentiation of follicular helper T (TFH) cells. We found an expansion of memory CD4+T cells in NLRX1 knock out (KO) mice compared to WT mice. Our RNA-sequencing analysis of memory CD4+ T cells showed increased expression of TFH signature genes in NLRX1 KO mice compared to WT mice. In line with this finding, NLRX1 KO mice exhibited an increase in TFH cells, germinal center (GC) B cells, and autoantibody production. Such cell expansion was driven by augmented production of IL-1β and mitochondrial reactive oxygen species (mROS), as TFH and GC B cells decreased in the presence of neutralizing IL-1β antibodies or mROS inhibitors in vivo. NLRX1 heterozygous (HET) MRL/lpr lupus-prone mice revealed exacerbated autoimmune phenotypes, including TFH cell expansion, elevated autoantibody production, and increased immune cell infiltration in the kidneys compared to control MRL/lpr mice. The results of our study support the role of NLRX1 in regulating T cell immunity, particularly the TFH differentiation program, which is critically involved in the pathogenesis of autoimmune diseases. Funding Sources Supported by NIH AG082433 for Insoo Kang Topic Categories Basic Autoimmunity (BA)