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 1

Immunodominant mouse collagen type II peptide mCII707–721 is CD1d restricted and activates CD4+TCRαβ+ NKT cells.

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Immunodominant mouse collagen type II peptide mCII707–721 is CD1d restri...
(A) Significant proliferative response was observed after in vitro peptide stimulation of LNCs from mCII707–721–immunized mice (WT B10.Q). Controls are medium or control peptide mCI707–721. Proliferation index (PI) was calculated by normalizing all cpm values to media control as 1. (B) PI in response to mCII707–721 in KO mice, all B10.Q background. Proliferation was significantly reduced compared with WT littermates in Tcrab–/–, CD4–/–, and CD1d–/– mice, indicating that the mCII707–721 peptide response depends on CD1d-restricted CD4+TCRαβ+ T cells, but not classical MHC I/II presentation. (C) PI in response to mCII707–721 in B10.Q LNCs. Blocking with anti–MHC II and anti–MHC I antibodies produced similar levels of PI compared with mCII707–721 with control antibody. PI was calculated by normalizing all cpm values to media control as 1. (D) In vitro rechallenge response to mCII707–721, abrogated by anti-CD1 (1B1, 10 μg/ml) or anti-NK1.1 (PK136, 10 μg/ml), indicating that CD1d-dependent NKT cells were operative in the response. PI was calculated by normalizing all cpm values to media control as 1. Data are mean ± SD, n = 6. **P ≤ 0.01; ***P ≤ 0.001.