Combination CTLA4Ig and anti-CD40L treatment modifies T and B cell metabolic profiles and promotes BCR and membrane protein remodeling in a mouse model of SLE

ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant morbidity - demanding further examination of tolerance inducing treatments. Short-term treatment of lupus-prone NZB/WF1 mice with combination CTLA4Ig and anti-CD40L but not single treatment alone, suppresses disease for > 6 months via modulation of B and T cell function while maintaining immune responses to exogenous antigens. Three months after a 2-week course of combination costimulatory blockade, we found a modest decrease in the number of activated T and B cells in both combination and single treatment cohorts compared to untreated controls. However, only combination treatment group showed a 50% decrease in spare respiratory capacity of splenic B and T cells. RNA-sequencing and gene set enrichment analysis of germinal center (GC) B cells confirmed a reduction in the oxidative phosphorylation signature in the combination treatment cohort. This cohort also manifested an increase in expression of B Cell Receptor (BCR) associated signaling molecules and an increase in phosphorylation of PLCγ in GC B cells after stimulation with anti-IgG and anti-CD40. GC B cells from combination treatment mice also displayed a signature involving remodeling of GPI-linked surface proteins. Accordingly, we found a decrease in cell surface expression of the inhibitory molecule CD24 on class-switched memory B cells from aged NZB/W mice that corrected in the combination treatment cohort. Since both a profound decrease in BCR signaling and increased immune cell metabolism enhance loss of tolerance in lupus-prone mice, our findings help to explain the restoration of tolerance observed after short-term combination costimulatory blockade.

ORGANISM(S): Mus musculus

PROVIDER: GSE181742 | GEO | 2022/12/19

REPOSITORIES: GEO