CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice
Sreya Bagchi, … , Johann E. Gudjonsson, Chyung-Ru Wang
Sreya Bagchi, … , Johann E. Gudjonsson, Chyung-Ru Wang
Published May 2, 2017
Citation Information: J Clin Invest. 2017;127(6):2339-2352. https://doi.org/10.1172/JCI92217.
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Research Article Autoimmunity Immunology

CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice

Abstract

A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe–/– mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe–/– mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti–IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid–reactive T cells might serve as a possible link between hyperlipidemia and psoriasis.

Authors

Sreya Bagchi, Ying He, Hong Zhang, Liang Cao, Ildiko Van Rhijn, D. Branch Moody, Johann E. Gudjonsson, Chyung-Ru Wang

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Figure 7

Phospholipid and cholesterol species, which preferentially accumulate in the skin of hCD1Tg HJ1Tg Apoe–/– mice, can activate HJ1 T cells.

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Phospholipid and cholesterol species, which preferentially accumulate in...
Total lipid was extracted from skin and liver tissues of mice, weighed, and analyzed by mass spectrometry and gas chromatography. (A) Comparison of phospholipid accumulation in the skin of diseased hCD1Tg HJ1Tg Apoe–/– and healthy hCD1Tg HJ1Tg Apoe+/+ mice. (B) Ratio of phospholipids from diseased over healthy mice in the skin and liver. PC, phosphatidylcholine; SM, sphingomyelin; DSM, dihydro-sphingomyelin; ePC, ether-linked phosphatidylcholine; PS, phosphatidylserine; PI, phosphatidylinositol; ePE, ether-linked phosphatidylethanolamine; ePS, ether-linked phosphatidylserine; PA, phosphatidic acid. (C) Comparison of apolar lipid accumulation in the skin of diseased hCD1Tg HJ1Tg Apoe–/– and healthy hCD1Tg HJ1Tg Apoe+/+ mice. (D) Ratio of apolar lipids from diseased over healthy mice in the skin and liver (n = 3). (E) Polar lipid extract (PL), cholesterol (Chol), and fatty acid mixtures (FA1 and FA2) were loaded onto CD1b protein and incubated with HJ1 T cell hybridoma for 24 hours. IL-2 in the supernatant was measured by ELISA. (F) CD1b-autoreactive human T cell clones were stained with mock-loaded CD1b tetramers or PG- or PE-loaded CD1b tetramers. Data are representative of at least 3 experiments. ***P < 0.005; **P < 0.01; *P < 0.05, Student’s t test.