Expansion of CD3+/CD4+/CD25+/Foxp3+ T cells in rapamycin-treated lupus patients (143.52)

Abstract

Abstract Activation and death pathway selection of T cells are regulated via the mitochondrial transmembrane potential (Δψm). Systemic lupus erythematosus (SLE) patients’ T cells exhibit persistent Δψm elevation or mitochondrial hyperpolarization (MHP) and ATP depletion which predispose them to pro-inflammatory death via necrosis. Here, we examined the role of the mammalian target of rapamycin (mTOR), which serves as a sensor of MHP, in T cell activation in 34 female SLE patients and 30 female controls matched for age and ethnicity. MHP and mitochondrial mass was most robustly (1.6-2.0-fold; p= 0.0027) increased in CD3+/CD4-/CD8- cells. The prevalence of Foxp3+ cells within the CD4+/CD25+ compartment was reduced in SLE patients (37.05 ± 3.0 %) relative to controls (48.37 ± 2.5 %; p = 0.0014). mTOR activity, as measured by the accumulation of pS6 protein, was increased > 1.5-fold in CD3+ T cells (p=0.012) and CD19+ B cells (p=0.006). Relative to healthy controls (3.18 ± 0.39%), the frequency of Foxp3+/CD4+/CD25+ cells was reduced in 6 lupus patients (1.70 ± 0.42%; p=0.021) prior to rapamycin treatment. In vivo treatment with rapamycin increased the frequency of Tregs from 1.50 ± 0.45% to 2.8 ± 0.59% (p=0.040) while the SLEDAI scores were reduced in 5 SLE patients from 22.4 ± 5.7 to 16.7 ± 2.8 (p=0.017).These data identify the in vivo expansion of Tregs as a potential mechanism of action that may contribute to the therapeutic efficacy of rapamycin in SLE.