Role of NK1.1+ and AsGm-1+ cells in oral immunoregulation of experimental colitis.
NK1.1 and AsGm-1 expressing cells play a role in immunomodulation. Our purpose was to determine the role of NK1.1+ and AsGm-1+ expressing cells in the inflammatory/tolerance paradigm in experimental colitis. Oral tolerance towards colitis-extracted proteins had previously been shown to alleviate experimental colitis. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Oral tolerance was induced via five oral doses of proteins extracted from TNBS-colitis colonic wall. Clinical, macroscopic, and microscopic scores were used for colitis assessment. To evaluate the putative role of AsGm-1 in tolerance induction, depletion of AsGm-1 expressing cells was performed. To evaluate the mechanism of tolerance induction, liver-associated NKT lymphocytes were harvested 14 days following tolerance induction, and cultured with concanavalin A (con A) and colitis-extracted proteins. T cell subsets were measured by flow cytometry. Cytokine expression was measured by intracellular staining and enzyme-linked immunosorbent assay (ELISA). Orally tolerized mice exhibited significant alleviation of the clinical, macroscopic, and microscopic parameters of colitis, with increased CD4+ILA+/CD4+IFNgamma+ lymphocyte ratio, increased IL-4, and decreased IFNgamma and IL-12 serum levels. In contrast, orally fed mice that were AsGm-1 depleted showed evidence of severe colitis. These mice exhibited significant decreased CD4 +IL4+/CD4+IFNgamma+ ratios, and an increase in IFNgamma and IL-12, with decreased IL-4 levels. NKT cells harvested from tolerized mice secreted high levels of antiinflammatory cytokines. In contrast, in nontolerized mice, NKT cells mainly secreted proinflammatory cytokines. In a tolerized environment, both NK1.1 and AsGm-1 expressing cells are essential for disease alleviation. In contrast, in a nontolerized environment, AsGm-1 expressing cells support an antiinflammatory immune paradigm, while NKT lymphocytes support a proinflammatory shift.
Trop
Shivti
S
Liver Unit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel.
Nagler
Arnon
A
Ilan
Yaron
Y
D000818:Animals; D000941:Antigens / Q000276:immunology; D000950:Antigens, Ly; D000954:Antigens, Surface; D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D003092:Colitis / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000502:physiology*; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011336:Probability; D011506:Proteins / Q000276:immunology; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D018417:Th1 Cells / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D037263:Asialoglycoprotein Receptor; D015415:Biomarkers; D016207:Cytokines; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D014302:Trinitrobenzenesulfonic Acid