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 6

DC function and phenotype under hyperlipidemic conditions.

Options: View larger image (or click on image) Download as PowerPoint
DC function and phenotype under hyperlipidemic conditions. (A) Pam3Cys-t...
(A) Pam3Cys-treated hCD1Tg, hCD1Tg Apoe–/–, and Apoe–/– LN–derived DCs were cultured in Apoe+/+ and Apoe–/– mouse serum. IL-6 was measured by cytometric bead array (CBA) after 48 hours. (B) hCD1Tg, hCD1Tg Apoe–/–, and Apoe–/– DCs were cocultured with hepatic HJ1 T cells from hCD1Tg HJ1Tg Rag–/– mice in Apoe+/+ and Apoe–/– serum for 48 hours. ELISA was used to measure IFN-γ and IL-17A secretion. Data are representative of at least 2 independent experiments. (C–E) Cells from the dermis were isolated, stained with various Abs, and gated on CD45 and CD11b+CD11c+ DCs. Percentages (C) and numbers (D) of CD1b-positive cells in the skin were quantified. (E) CD1b+DCs (gated on CD11b+CD11c+ population) were examined for their expression of costimulatory molecule CD86 (n = 4). ***P < 0.005; **P < 0.01; *P < 0.05. Statistical analyses were performed using 1-way ANOVA followed by Bonferroni’s post-hoc test for 3 group comparisons and Student’s t test for 2 group comparisons.