T cell-specific deletion of Glutaminase (Gls1) lowers autoantibody production by altering the metabolic profile and regulating the function of follicular helper T cells in lupus-prone mice 2595

Abstract Description Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by high-affinity class-switched autoantibodies (autoAb) generated by germinal center (GC) age-associated B cells (ABC) with follicular helper T (Tfh) cell assistance. Cellular metabolism of Tfh cells, particularly glutamine, is altered in SLE. Pharmacological inhibition of GLS1, the first glutaminolysis enzyme, decreased Tfh cell function, GC size, and ABC frequency to healthy control levels and decreased autoAb production in lupus mice. Our novel T cell-specific Gls1 deletion in autoimmune B6.Sle1b (Sle1b Gls1 KO) mice extended these findings, showing that T cell-specific Gls1 deletion alone reduces autoAb production and GC and ABC expansion in SLE-prone mice, underscoring the critical, T cell-intrinsic role of glutamine metabolism in pathogenic Tfh cell function. ICOS, a critical molecule in Tfh-B cell interactions, was downregulated on Tfh cells by both pharmacological and genetic inhibition of GLS1. This suggests glutamine metabolism may regulate ICOS expression, supporting Tfh differentiation and function. Further, metabolic analysis of Sle1b Gls1 KO CD4+ T cells showed decreased glycolysis, respiration, and spare respiratory capacity compared to control Sle1b mice, highlighting a unique shift in metabolic demand. In contrast, B6 mice were minimally affected by Gls1 deletion in T cells. These findings underscore glutaminolysis as a key pathway supporting pathogenic Tfh cell function in SLE. Funding Sources Supported by NIH R37AI128901 Topic Categories Basic Autoimmunity (BA)