Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice.

BACKGROUND & AIMS CD1d is a major histocompatibility complex class I-like molecule that presents glycolipid antigens to a subset of natural killer (NK)1.1(+) T cells. These NK T cells exhibit important immunoregulatory functions in several autoimmune disease models. METHODS To investigate whether CD1d and NK T cells have a similar role in intestinal inflammation, the effects of the glycolipid, alpha-galactosylceramide (alpha-GalCer), on dextran sodium sulfate (DSS)-induced colitis were examined. Wild-type (WT), CD1d(-/-), and RAG(-/-) mice were examined for their response to either alpha-GalCer or the control analogue, alpha-mannosylceramide (alpha-ManCer). RESULTS WT mice, but not CD1d(-/-) and RAG(-/-) mice, receiving alpha-GalCer had a significant improvement in DSS-induced colitis based on body weight, bleeding, diarrhea, and survival when compared with those receiving alpha-ManCer. Elimination of NK T cells through antibody-mediated depletion resulted in a reduction of the effect of alpha-GalCer. Furthermore, adoptive transfer of NK T cells preactivated by alpha-GalCer, but not alpha-ManCer, resulted in diminished colitis. Using a fluorescent-labeled analogue of alpha-GalCer, confocal microscopy localized alpha-GalCer to the colonic surface epithelium of WT but not CD1d(-/-) mice, indicating alpha-GalCer binds CD1d in the intestinal epithelium and may be functionally active at this site. CONCLUSIONS These results show an important functional role for NK T cells, activated by alpha-GalCer in a CD1d-restricted manner, in regulating intestinal inflammation.

[1]  R. Hershberg,et al.  Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Snapper,et al.  Cd1-Reactive Natural Killer T Cells Are Required for Development of Systemic Tolerance through an Immune-Privileged Site , 1999, The Journal of experimental medicine.

[3]  L. Kaer,et al.  Cutting edge: activation of NK T cells by CD1d and alpha-galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype. , 1999, Journal of immunology.

[4]  Y. Koezuka,et al.  Synthesis of NBD-alpha-galactosylceramide and its immunologic properties. , 1999, Organic letters.

[5]  M. Kronenberg,et al.  Immunization with α‐galactosylceramide polarizes CD1‐reactive NK T cells towards Th2 cytokine synthesis , 1999, European journal of immunology.

[6]  S. Balk,et al.  Immunolocalization of CD1d in human intestinal epithelial cells and identification of a beta2-microglobulin-associated form. , 1999, International immunology.

[7]  G. Churchill,et al.  Genetic analysis of susceptibility to dextran sulfate sodium-induced colitis in mice. , 1999, Genomics.

[8]  D. Doherty,et al.  Natural T cells in the human liver: cytotoxic lymphocytes with dual T cell and natural killer cell phenotype and function are phenotypically heterogenous and include Vα24-JαQ and γδ T cell receptor bearing cells , 1999 .

[9]  S. Porcelli,et al.  The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. , 1999, Annual review of immunology.

[10]  E. Bloemena,et al.  Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines , 1998, Clinical and experimental immunology.

[11]  M. Kronenberg,et al.  Structural requirements for galactosylceramide recognition by CD1-restricted NK T cells. , 1998, Journal of immunology.

[12]  M. Kronenberg,et al.  CD1d-mediated Recognition of an α-Galactosylceramide by Natural Killer T Cells Is Highly Conserved through Mammalian Evolution , 1998, The Journal of experimental medicine.

[13]  M. Leach,et al.  A role for NK cells as regulators of CD4+ T cells in a transfer model of colitis. , 1998, Journal of immunology.

[14]  S. Balk,et al.  CD161 (NKR-P1A) Costimulation of CD1d-dependent Activation of Human T Cells Expressing Invariant Vα24JαQ T Cell Receptor α Chains , 1998, The Journal of experimental medicine.

[15]  A. Bylund-Fellenius,et al.  Experimental colitis induced by dextran sulphate sodium in mice: beneficial effects of sulphasalazine and olsalazine , 1998, Alimentary pharmacology & therapeutics.

[16]  C. Fiocchi.  Inflammatory bowel disease: etiology and pathogenesis. , 1998, Gastroenterology.

[17]  K. Imai,et al.  Structural organization of rat CD1 typifies evolutionarily conserved CD1D class genes , 1998, Immunogenetics.

[18]  D. Godfrey,et al.  α/β–T Cell Receptor (TCR)+CD4−CD8− (NKT) Thymocytes Prevent Insulin-dependent Diabetes Mellitus in Nonobese Diabetic (NOD)/Lt Mice by the Influence of Interleukin (IL)-4 and/or IL-10 , 1998, The Journal of experimental medicine.

[19]  P. Peters,et al.  The tyrosine-containing cytoplasmic tail of CD1b is essential for its efficient presentation of bacterial lipid antigens. , 1998, Immunity.

[20]  J. Sundberg,et al.  Differential susceptibility of inbred mouse strains to dextran sulfate sodium-induced colitis. , 1998, American journal of physiology. Gastrointestinal and liver physiology.

[21]  D. Hafler,et al.  Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes , 1998, Nature.

[22]  Hiroshi Sato,et al.  Requirement for Vα14 NKT Cells in IL-12-Mediated Rejection of Tumors , 1997 .

[23]  Hiroshi Sato,et al.  CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. , 1997, Science.

[24]  Hervé Groux,et al.  A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis , 1997, Nature.

[25]  W. Paul,et al.  Cultured NK1.1+ CD4+ T cells produce large amounts of IL-4 and IFN-gamma upon activation by anti-CD3 or CD1. , 1997, Journal of immunology.

[26]  S. Ichimiya,et al.  Localization of rat CD1 transcripts and protein in rat tissues— an analysis of rat CD1 expression by in situ hybridization and immunohistochemistry , 1997, Clinical and experimental immunology.

[27]  S. Balk,et al.  Requirements for CD1d Recognition by Human Invariant Vα24+ CD4−CD8− T Cells , 1997, The Journal of experimental medicine.

[28]  Seokmann Hong,et al.  CD1d1 mutant mice are deficient in natural T cells that promptly produce IL-4. , 1997, Immunity.

[29]  M. Kaplan,et al.  Immunoglobulin E Production in the Absence of Interleukin-4-Secreting CD1-Dependent Cells , 1997, Science.

[30]  S. Park,et al.  Mouse CD1-specific NK1 T cells: development, specificity, and function. , 1997, Annual review of immunology.

[31]  A. Bylund-Fellenius,et al.  Dextran sulfate sodium (DSS) induces experimental colitis in CD4(+)-cell depleted, athymic and NK-cell depleted scid mice. , 1996 .

[32]  W. Paul,et al.  Role of NK1.1+ T Cells in a TH2 Response and in Immunoglobulin E Production , 1995, Science.

[33]  A. Chott,et al.  Structure and Function of the CD1 Family of MHC‐like Cell Surface Proteins , 1995, Immunological reviews.

[34]  C. Elson,et al.  Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. , 1994, Gastroenterology.

[35]  W. Havran,et al.  Modulation of epithelial cell growth by intraepithelial gamma delta T cells. , 1994, Science.

[36]  H. Macdonald,et al.  Major histocompatibility complex class I related molecules control the development of CD4+8- and CD4-8- subsets of natural killer 1.1+ T cell receptor-alpha/beta+ cells in the liver of mice , 1994, The Journal of experimental medicine.

[37]  H. Cooper,et al.  Clinicopathologic study of dextran sulfate sodium experimental murine colitis. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[38]  S. Balk,et al.  Expression of a nonpolymorphic MHC class I-like molecule, CD1D, by human intestinal epithelial cells. , 1991, Journal of immunology.

[39]  S. Balk,et al.  Isolation and expression of cDNA encoding the murine homologues of CD1. , 1991, Journal of immunology.

[40]  T. Flotte,et al.  Expression of murine CD1 on gastrointestinal epithelium. , 1990, Science.

[41]  C. Terhorst,et al.  Isolation and characterization of a cDNA and gene coding for a fourth CD1 molecule. , 1989, Proceedings of the National Academy of Sciences of the United States of America.