Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients
Georgia McDonald, … , Terry Butters, Elizabeth C. Jury
Georgia McDonald, … , Terry Butters, Elizabeth C. Jury
Published January 27, 2014
Citation Information: J Clin Invest. 2014;124(2):712-724. https://doi.org/10.1172/JCI69571.
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Research Article

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

Abstract

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

Authors

Georgia McDonald, Shantal Deepak, Laura Miguel, Cleo J. Hall, David A. Isenberg, Anthony I. Magee, Terry Butters, Elizabeth C. Jury

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Figure 3

Upregulation of LXRβ by oxysterol and TCR stimulation.

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Upregulation of LXRβ by oxysterol and TCR stimulation. (A) CD4+ T cells ...
(A) CD4+ T cells from 3 healthy donors and 3 SLE patients were cultured for 18 hours with GW3965 or CM and analyzed by Western blotting for LXRβ expression. (B) Cumulative data. Paired and 2-tailed Student’s t test; *P ≤ 0.05. (C) CD4+ T cells from 5 healthy donors and 5 SLE patients cultured for 18 hours with GW3965 or CM were assessed by qPCR for LXRB expression. Cumulative results comparing LXRB with GAPDH control. Paired and 2-tailed Student’s t tests; *P ≤ 0.05. PBMCs from a healthy donor were cultured for 72 hours (all plus IL-2) with serum from 5 heterologous healthy donors (HC serum), 5 SLE patients (SLE serum), or with CM only (MO). (D) Cumulative data. One-way ANOVA; *P = 0.05. (E) CD4+ T cells from 5 healthy donors were cultured for 72 hours with LDL, oxidized LDL (oxLDL), or CM before CTB staining. Representative histograms and cumulative data. One-way ANOVA; *P ≤ 0.01. (F) PBMCs from a healthy donor were cultured with serum from 12 healthy donors, 12 SLE patients, or with CM (all plus IL-2) (for 72 hours and for 10 days) and stained with CTB. Cumulative data showing percentage change from CM. One-way ANOVA; *P ≤ 0.05. (G) PBMCs from 4 SLE patients and 4 healthy donors were cultured for 3 days with GW3965 ± the LXR antagonist 5CPPSS-50 and stained with CTB. One-way ANOVA; *P ≤ 0.05. (H) PBMCs from a healthy donor were cultured for 10 days as described in F with serum from 4 SLE patients ± 5CPPSS-50 and stained with CTB. One-way ANOVA; *P = 0.03.