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 8

mCII707–721–specific NKT cells have a suppressive function.

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mCII707–721–specific NKT cells have a suppressive function. (A and B...
(A and B) Suppressor assay was performed using in vitro–stimulated anti-CD3 splenocytes (responder cells) from B10.Q mice, cocultured for 64 hours with either mCII707–721–specific NKT cell line or B10.Q-restricted MOG79–96–specific T cell line (control) at a 1:1 ratio. Proliferation index was calculated by normalizing all cpm values to media control as 1. (A) Blocking IFN-γ, IL-4, TGF-β1, and TGF-β receptor with antibodies (20 μg/ml) had no effect on NKT cell suppression compared with isotype-matched controls; therefore suppression did not operate through cytokine release from mCII707–721–specific NKT cells. Data are mean ± SD, n = 3. *P ≤ 0.05; ***P ≤ 0.001. (B) Significantly reduced proliferation of anti-CD3–stimulated responder cells was observed when cultured with the mCII707–721–specific NKT cells (with or without Transwell system) compared with control cells. Proliferation of the responder cells was restored when a Transwell system inhibited cell-cell contact. Data are mean ± SD, n = 2–3. **P ≤ 0.01; ***P ≤ 0.001. (C) Cell death by annexin V+ FACS analysis of cocultured splenocytes (CFSE labeled), showing that the mCII707–721–specific NKT cell line induced significantly elevated cell death levels compared with the control cells. Anti-FasL (20 μg/ml) before coculturing revealed that splenocyte killing was mediated by FasL interaction. Data are mean ± SD, n = 3. **P ≤ 0.01. (D) Splenocytes (CFSE labeled) from WT mice stimulated with plate-bound anti-CD3 and cocultured for 48 hours with NKT cells purified from mCII707–721–immunized WT mice or lpr mice. Cell death was determined by 7AAD staining. Data are mean ± SD, n = 10 mice per group. **P ≤ 0.01.