title: Pathogenicity of T helper 2 T-cell clones from T-cell receptor transgenic non-obese diabetic mice is determined by tumour necrosis factor-alpha.
abstract: Autoimmune diabetes is predominated by a T helper 1 (Th1) response at the expense of an impaired Th2 response. Although T cells producing Th2 cytokines are generally thought to counter a Th1 response, there have been reports of Th2 T-cell clones with pathogenic activity, including one previously reported by us in which the Th2 T-cell clone was derived from a T-cell receptor transgenic (TCR-Tg) mouse bearing pathogenic TCR. In this study, our goal was to determine whether Th2 T-cell clones derived from a TCR-Tg in which the autoantigen was absent would be pathogenic and if so, to investigate possible mechanisms by which the Th2 T-cell clone could promote disease. We found that a Th2 T-cell clone derived from the 6.9 TCR-Tg/non-obese diabetic (NOD).C6 mouse in which 6.9 T cells do not encounter autoantigen, produced Th2 cytokines but not interferon-gamma. This Th2 T-cell clone, like the previous one we had isolated from the 2.5 TCR-Tg/NOD mouse, also turned out to be pathogenic. Intracellular staining revealed that these Th2 T-cell clones produce low levels of tumour necrosis factor-alpha (TNF-alpha) in vitro, and after adoptive transfer, they migrate to the pancreas where they produce TNF-alpha as well as Th2 cytokines (interleukin (IL)-4, IL-10). Induction of disease was prevented by administration of soluble TNF-alpha receptor to recipient mice, suggesting that the diabetogenicity of these Th2 T-cell clones is caused by their low level production of TNF-alpha.
authors.affiliation: Department of Immunology, University of Colorado Health Sciences Center/National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Kathryn
authors.initials: K
authors.lastname: Haskins
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002478:Cells, Cultured; D002999:Clone Cells / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D060889:Inducible T-Cell Co-Stimulator Protein; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D018418:Th2 Cells / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide