Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis.
Journal: 2004/June - Journal of Clinical Investigation
ISSN: 0021-9738
Abstract:
While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its counterpart inflammatory bowel disease, ulcerative colitis (UC), remains enigmatic. Here we show that lamina propria T (LPT) cells from UC patients produce significantly greater amounts of IL-13 (and IL-5) than control cells and little IFN-gamma, whereas comparable cells from CD patients produce large amounts of IFN-gamma and small amounts of IL-13. We then show that stimulation of UC LPT cells bearing an NK marker (CD161) with anti-CD2/anti-CD28 or with B cells expressing transfected CD1d induces substantial IL-13 production. While this provided firm evidence that the IL-13-producing cell is an NK T (NKT) cell, it became clear that this cell does not express invariant NKT cell receptors characteristic of most NKT cells since there was no increase in cells binding alpha-galactosylceramide-loaded tetramers, and alpha-galactosylceramide did not induce IL-13 secretion. Finally, we show that both human NKT cell lines as well as UC CD161(+) LPT cells are cytotoxic for HT-29 epithelial cells and that this cytotoxicity is augmented by IL-13. These studies show that UC is associated with an atypical Th2 response mediated by nonclassical NKT cells producing IL-13 and having cytotoxic potential for epithelial cells.
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J Clin Invest 113(10): 1490-1497

Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis

+3 authors
Mucosal Immunity Section, NIH, Bethesda Maryland, USA. Laboratory of Immunology, Istituto Superiore di Sanit¤, Rome, Italy. Immune Cell Interaction Unit, NIH, Bethesda, Maryland, USA. Division of Gastroenterology, Brigham and Women’s Hospital, Boston Massachusetts, USA. Cancer Biology Program, Hematology/Oncology Division, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Ivan J. Fuss, Mucosal Immunity Section, National Institutes of Health, 10 Center Drive, Building 10, Room 11N238, Bethesda, Maryland 20892, USA. Phone: (301) 496-6810; Fax: (301) 402-2240; E-mail: vog.hin.diain@ssufi.
Address correspondence to: Ivan J. Fuss, Mucosal Immunity Section, National Institutes of Health, 10 Center Drive, Building 10, Room 11N238, Bethesda, Maryland 20892, USA. Phone: (301) 496-6810; Fax: (301) 402-2240; E-mail: vog.hin.diain@ssufi.
Received 2003 Aug 19; Accepted 2004 Mar 23.

Abstract

While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its counterpart inflammatory bowel disease, ulcerative colitis (UC), remains enigmatic. Here we show that lamina propria T (LPT) cells from UC patients produce significantly greater amounts of IL-13 (and IL-5) than control cells and little IFN-γ, whereas comparable cells from CD patients produce large amounts of IFN-γ and small amounts of IL-13. We then show that stimulation of UC LPT cells bearing an NK marker (CD161) with anti-CD2/anti-CD28 or with B cells expressing transfected CD1d induces substantial IL-13 production. While this provided firm evidence that the IL-13–producing cell is an NK T (NKT) cell, it became clear that this cell does not express invariant NKT cell receptors characteristic of most NKT cells since there was no increase in cells binding α-galactosylceramide–loaded tetramers, and α-galactosylceramide did not induce IL-13 secretion. Finally, we show that both human NKT cell lines as well as UC CD161 LPT cells are cytotoxic for HT-29 epithelial cells and that this cytotoxicity is augmented by IL-13. These studies show that UC is associated with an atypical Th2 response mediated by nonclassical NKT cells producing IL-13 and having cytotoxic potential for epithelial cells.

Abstract

Acknowledgments

The authors would like to thank Claudio Fiocchi for his extremely helpful technical support of this project. The authors would also like to thank Sara Kaul for her editorial assistance. R.S. Blumberg was supported by NIH DK-44319, 51362, and 53056 and the Harvard Digestive Diseases Center. M. Boirivant was partially supported by grant 1130/RI from the Italian Ministry of Health. This manuscript is dedicated to the memory of Abraham Fuss.

Acknowledgments

Footnotes

Frank Heller’s present address is: Department of Gastroenterology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany.

Ivan J. Fuss and Frank Heller contributed equally to this work.

Nonstandard abbreviations used: 721.221 cell line (721 cells); concanavalin A (conA); Crohn disease (CD); effector-to-target ratio (E/T); α-galactosylceramide (α-GalCer); inflammatory bowel disease (IBD); intestinal epithelial cell (IEC); invariant NKT (iNKT); lamina propria mononuclear cell (LPMC); NK T (NKT); phycoerythrin (PE); T cell receptor (TCR); ulcerative colitis (UC).

Conflict of interest: The authors have declared that no conflict of interest exists.

Footnotes

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