title: Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3(+) regulatory T cells specific for the ubiquitous RNA-binding nuclear antigen La/Sjögren's syndrome (SS)-B.
abstract: RNA-binding nuclear antigens are a major class of self-antigen to which immune tolerance is lost in rheumatic diseases. Serological tolerance to one such antigen, La/Sjögren's syndrome (SS)-B (La), is controlled by CD4(+) T cells. This study investigated peripheral tolerance to human La (hLa) by tracking the fate of hLa-specific CD4(+) T cells expressing the transgenic (Tg) 3B5.8 T cell receptor (TCR) after adoptive transfer into lymphocyte-replete recipient mice expressing hLa as a neo-self-antigen. After initial antigen-specific cell division, hLa-specific donor CD4(+) T cells expressed forkhead box protein 3 (FoxP3). Donor cells retrieved from hLa Tg recipients displayed impaired proliferation and secreted interleukin (IL)-10 in vitro in response to antigenic stimulation. Transfer of highly purified FoxP3-negative donor cells demonstrated that accumulation of hLa-specific regulatory T cells (Treg ) was due primarily to expansion of small numbers of donor Treg . Depletion of recipient plasmacytoid dendritic cells (pDC), but not B cells, severely hampered the accumulation of FoxP3(+) donor Treg in hLa Tg recipients. Recipient pDC expressed tolerogenic markers and higher levels of co-stimulatory and co-inhibitory molecules than B cells. Adoptive transfer of hLa peptide-loaded pDC into mice lacking expression of hLa recapitulated the accumulation of hLa-specific Treg . Blockade of the type 1 interferon (IFN) receptor in hLa Tg recipients of hLa-specific T cells impaired FoxP3(+) donor T cell accumulation. Therefore, peripheral expansion of Treg specific for an RNA-binding nuclear antigen is mediated by antigen-presenting pDC in a type 1 IFN-dependent manner. These results reveal a regulatory function of pDC in controlling autoreactivity to RNA-binding nuclear antigens.
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Pan
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation.|Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City.|Department of Biological Sciences, Southwestern Oklahoma State University, Weatherford, OK, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Horton
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation.
authors.forename: C
authors.initials: C
authors.lastname: Lawrence
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation.|Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: A D
authors.initials: AD
authors.lastname: Farris
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012261:Ribonucleoproteins / Q000276:immunology*; D012859:Sjogren's Syndrome / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D000097585:SS-B Antigen
chemical_list: D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; D007370:Interferon Type I; D012261:Ribonucleoproteins; D000097585:SS-B Antigen; C498833:Foxp3 protein, mouse
keywords: La/SS-B; plasmacytoid dendritic cell; regulatory T cell; type 1 interferon