Plasmacytoid dendritic cells and type 1 IFN promote peripheral expansion of Foxp3+ regulatory T cells specific for the ubiquitous RNA‐binding nuclear antigen La/SS‐B
2016
RNA-binding nuclear antigens are a major class of self-antigen to which immune tolerance is lost in rheumatic diseases. Serologic tolerance to one such antigen, La/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 Foxp3. Donor cells retrieved from hLa Tg recipients displayed impaired proliferation and secreted 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 primarily due 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. This article is protected by copyright. All rights reserved.
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