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

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 3

mCII707–721 induces NKT cell expansion.

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mCII707–721 induces NKT cell expansion. (A and B) Splenocytes were t...
(A and B) Splenocytes were taken from naive WT (B10.Q) mice and in vivo CFA-, mCI707–721–, and mCII707–721–treated mice. Single-cell suspensions were made and then stimulated with 100 μg/ml mCII707–721 for 48 hours. n = 3 mice per group. (A) A representative FACS staining shows total gated lymphocytes (upper row) and gated CD4+NK1.1+ NKT cells (lower row). (B) Percentage of CD4+NK1.1+ NKT cells from indicated groups. Data are mean ± SD, n = 3. **P ≤ 0.01; ***P ≤ 0.001. (C) Proportion of NK1.1+ T cells in cell line during the first stimulation of LNCs (57%), and after 2 (65%) and 3 (88%) in vitro stimulation cycles with mCII707–721. NK1.1+ T cells enriched after each stimulation, indicating response and proliferation after mCII707–721 exposure. Data are mean ± SD. n = 3. (D) mCII707–721–specific cell line characterized for TCR usage after 3 stimulation cycles with a significantly higher proportion of Vα14-Jα18 by real-time qPCR compared with control BQMOG79–96–specific T cells (top panel). Vα14 PCR product in agarose gel is shown (bottom panel). Data are mean ± SD. n = 3. ***P ≤ 0.001. (E) Splenocytes were taken from mCII707–721–immunized mice treated with 100 μg/ml mCII707–721 for 48 hours. FACS staining shows TCR Vβ usage. Percentages were computed relative to the sum of all of the 15 chains. Data are mean ± SD, n = 3.