title: DRB1*0402 may influence arthritis by promoting naive CD4+ T-cell differentiation in to regulatory T cells.
abstract: HLA-DRB1*0401 expression in humans has been associated with a predisposition to developing rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), while HLA-DRB1*0402 is not associated with susceptibility. Here, we determined if mice transgenic (Tg) for human *0401 have a CD4+ T-cell repertoire that predetermines proinflammatory cytokine production. The data show that both *0401 and *0402 Tg mice can produce TH1/TH17 cytokines, although the kinetics of response may be different. However, in the context of antigen-specific responses in a CIA model, *0402 Tg mice generate a TH2 response that may explain their resistance to developing arthritis. In addition, a significant subset of naïve CD4+ T cells from *0402 Tg mice can be activated in polarizing conditions to differentiate into Treg cells that produce IFN-γ. *0401 Tg mice harbor memory CD4+ T cells that differentiate into IL-17(+) cells in various polarizing conditions. Our data suggest that *0401 Tg mice generate a strong immune response to lipopolysaccharide and may be efficient in clearing infection, and may *0401 have been evolutionarily selected for this ability. Autoimmunity, such as RA, could likely be a bystander effect of the cytokine storm that, along with the presence of low Treg-cell numbers in *0401 Tg mice, causes immune dysregulation.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David
authors.initials: D
authors.lastname: Luckey
authors.forename: Marshall
authors.initials: M
authors.lastname: Behrens
authors.forename: Michele
authors.initials: M
authors.lastname: Smart
authors.forename: Harvinder
authors.initials: H
authors.lastname: Luthra
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Veena
authors.initials: V
authors.lastname: Taneja
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; C553506:HLA-DRB1*04:02 antigen; D020381:Interleukin-17; D008070:Lipopolysaccharides
keywords: Humanized mice; Immune dysregulation; Regulatory T cells; Rheumatoid arthritis; T-cell polarization
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