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.

IDO1 and TGF-β Mediate Protective Effects of IFN-α in Antigen-Induced Arthritis

“…1, 3A, 4A, 7A) is by promotion of regulatory T cells (Tregs) with ability to restrain inflammation (33). pDC may employ type I IFN signaling to induce Tregs (34), and this ability has been shown to require the enzymatic activity of IDO1 (35). By generating Kyn from Trp, IDO1 + pDC can activate the aryl hydrocarbon receptor on naive T cells, which favors their development into Foxp3 + Tregs.…”

Innate immunity in Sjögren's syndrome

“…Mice injected systemically with an inflammatory stimulus exhibit salivary gland dysfunction that correlates with increased frequency of pDCs in the gland [60]. Importantly, a recent study suggests that these cells may also serve a tolerogenic role in SS, as pDCS and IFNα promote the expansion of regulatory T cells that have specificity for the SS autoantigen La [61]. Thus, further studies are needed to determine whether pDCs are primarily pathogenic or protective in disease.…”

Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms

“…In this stage, the proliferation and amplification of T cells in the ocular surface cause injury, restart the acute proinflammatory innate response, and with the loss of immune regulation, trigger a vicious cycle of pathological immune response (Baudouin, 2001). DC is the most powerful known APC that can activate initial T cells, and play a dual role in the initiation and regulation of immune response, connecting innate immunity and adaptive immunity (Hackstein et al, 2016;Pan et al, 2016). In diabetes-associated dry eyes, advanced glycosylation end products can directly promote the maturation of DC and induce specific immune response of CD4 + T cells, and the increased number and abnormal function of DC can induce adaptive immune response.…”