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Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates tissue-specific inflammation in mice
Yawei Liu, … , Rikard Holmdahl, Shohreh Issazadeh-Navikas
Yawei Liu, … , Rikard Holmdahl, Shohreh Issazadeh-Navikas
Published December 13, 2010
Citation Information: J Clin Invest. 2011;121(1):249-264. https://doi.org/10.1172/JCI43964.
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Research Article Immunology

Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates tissue-specific inflammation in mice

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Abstract

NKT cells in the mouse recognize antigen in the context of the MHC class I–like molecule CD1d and play an important role in peripheral tolerance and protection against autoimmune and other diseases. NKT cells are usually activated by CD1d-presented lipid antigens. However, peptide recognition in the context of CD1 has also been documented, although no self-peptide ligands have been reported to date. Here, we have identified an endogenous peptide that is presented by CD1d to activate mouse NKT cells. This peptide, the immunodominant epitope from mouse collagen type II (mCII707–721), was not associated with either MHC class I or II. Activation of CD1d-restricted mCII707–721–specific NKT cells was induced via TCR signaling and classical costimulation. In addition, mCII707–721–specific NKT cells induced T cell death through Fas/FasL, in an IL-17A–independent fashion. Moreover, mCII707–721–specific NKT cells suppressed a range of in vivo inflammatory conditions, including delayed-type hypersensitivity, antigen-induced airway inflammation, collagen-induced arthritis, and EAE, which were all ameliorated by mCII707-721 vaccination. The findings presented here offer new insight into the intrinsic roles of NKT cells in health and disease. Given the results, endogenous collagen peptide activators of NKT cells may offer promise as novel therapeutics in tissue-specific autoimmune and inflammatory diseases.

Authors

Yawei Liu, Anna Teige, Emma Mondoc, Saleh Ibrahim, Rikard Holmdahl, Shohreh Issazadeh-Navikas

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Figure 2

mCII707–721 binds CD1d.

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mCII707–721 binds CD1d.
   
(A) The binding capacity of mCII707–721 to C...
(A) The binding capacity of mCII707–721 to CD1d was determined using ELISA plates coated with CD1d-Ig dimer, with biotin-labeled anti-CD1d (bio–anti-CD1) (positive control), biotin-labeled mCII707–721 peptide, or biotin-labeled mCI707–721 (negative control). Excess nonlabeled mCII707–721 peptide with biotin-labeled mCII707–721 peptide was used for competitive binding. Significant differences were seen in wells with biotin-labeled mCII707–721 peptide compared with negative control or excess nonlabeled peptide. (B) mCII707–721 binding to CD1d was concentration dependent, with a maximum binding capacity of 0.6 μg/ml. Ratio of binding is the fluorometer OD of the sample divided by the positive control OD. (C) αGalCer and biotinylated-labeled mCII707–721 peptide compete for binding to CD1d. Biotinylated-labeled mCII707–721 peptide binding to CD1d is considered as 100% binding. Data are mean ± SD, n = 3–4. **P ≤ 0.01; ***P ≤ 0.001.

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

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