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 4

T cells in hCD1Tg HJ1Tg Apoe–/– mice produce elevated levels of IL-17A.

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T cells in hCD1Tg HJ1Tg Apoe–/– mice produce elevated levels of IL-17A. ...
Dermal and LN cells from indicated mice were stimulated with PMA/ionomycin to measure intracellular cytokine secretion. Cells were gated on CD45+ and TCRβ+ populations. (A) Representative FACS plots of IL-17A–producing T cells in the dermis (upper panels) and cervical LNs (lower panels) in indicated mice. (B and C) Bar graphs (mean + SEM) depict the percentages of IL-17A–producing T cells in the dermis (B) and cervical LNs (C). (D) Representative FACS plots of IFN-γ–producing T cells in the dermis and cervical LNs. (E and F) Quantification of IFN-γ–producing T cells in the dermis (E) and cervical LNs (F) (n = 4–5). (G) WT (hCD1Tg–) and hCD1Tg+ BMDCs were cocultured with enriched T cells from either hCD1Tg HJ1Tg Apoe+/+ or hCD1Tg HJ1Tg Apoe–/– mice for 48 hours. Amount of IL-17A (left panel) and IFN-γ (right panel) was determined by ELISA. Data are representative of 3 independent experiments. (H) T cells were enriched from hCD1Tg and hCD1Tg Apoe–/– mice and cocultured with WT or hCD1Tg+ DCs for 24 hours. IL-17A–producing cells were quantified by ELISPOT assays. Data are representative of 2 independent experiments. ***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.