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.
View: Text | PDF
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

×

Figure 2

Diseased skin in hCD1Tg HJ1Tg Apoe–/– mice is characterized by T cell and neutrophil infiltrates.

Options: View larger image (or click on image) Download as PowerPoint
Diseased skin in hCD1Tg HJ1Tg Apoe–/– mice is characterized by T cell an...
Indicated organs were harvested from mice at about 25 weeks of age when hCD1Tg HJ1Tg Apoe–/– mice exhibited fulminant disease. (A and B) Immunofluorescence staining of skin sections from indicated mice with anti-CD3 (A) and anti–Gr-1 (B). Scale bars: 100 μm. (C) Bar graph depicts the absolute number of various leukocyte subsets in the dermis of mice, performed using flow cytometry (n = 3–5). (D) mRNA analysis of HJ1 T cells in the skin of the mice using HJ1 TCR–specific primers. (E–G) hCD1Tg HJ1Tg Apoe–/– mice have systemic neutrophil infiltration. Quantification of neutrophils (CD11b+Ly6G+cells) in the cervical LNs (E), spleen (F), and liver (G) was performed using flow cytometry (n = 4–6). (H) mRNA detected in the skin of different mouse strains using cytokine-specific primers (n = 3–5). mRNA levels were normalized relative to β-actin. Values are mean + SEM. ***P < 0.005; **P < 0.01. Statistical analyses were performed using 1-way ANOVA followed by Bonferroni’s post-hoc test.