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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 Article has an altmetric score of 20

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

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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 7

NB-DNJ modifies TCR-associated defects in T cells from patients with SLE.

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NB-DNJ modifies TCR-associated defects in T cells from patients with SLE...
PBMCs from 5 SLE patients and 5 healthy donors were cultured for 7 days with NB-DNJ. Cells were labeled with anti-CD3/CD28 (1 μg/ml) and cross-linking anti-mouse IgG on ice before culturing at 37°C for 1 and 5 minutes. Cells were fixed and labeled with fluorescent barcoding reagents and stained for CD4-APC and intracellularly stained for the phosphorylated signaling proteins pTCR-ζ, pERK, pAKT, and pNF-κB. (A) Cumulative results from three separate experiments. Two-tailed Student’s t test; *P ≤ 0.05 or paired t test; **P = 0.001. PBMCs from 24 SLE patients and 11 healthy donors were TCR stimulated for 72 hours with anti-CD3/CD28 (1 μg/ml) with or without 10 μM NB-DNJ. Cell culture supernatants were collected. Cells were surface stained with CD4-v450 and intracellularly stained for Ki67-PE and assessed by flow cytometry. (B) Representative flow cytometric dot plots (C) and cumulative results showing Ki67 expression as the percentage change from unstimulated controls. Two-tailed Student’s t test; *P ≤ 0.05. Cell culture supernatants from 12 SLE patients and 10 healthy donors collected from B were analyzed by CBA. Representative CBA plots (D) and cumulative data (E) are shown. Two-tailed Student’s t test and paired t test; *P ≤ 0.05. (F) CD4+ T cells isolated from 4 SLE patients were pretreated with NB-DNJ, then cocultured with autologous B cells for 7 days in the presence of anti-CD3 (1 μg/ml). The production of anti-dsDNA antibodies was detected by ELISA. Paired Student’s t test; *P ≥ 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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