Session Type: Abstract Submissions (ACR)
A prominent interferon-α (IFNα) signature is seen in several autoimmune diseases including systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) are the main IFNα producing cells and produce large amounts of IFNα in response to immune complexes containing nucleic acids (ICs). Produced IFNα activates the immune system in a number of ways, including polarization of naïve T helper cells to Th1 cells, expansion and activation of cytotoxic CD8+ T cells and enhanced B-cell differentiation and antibody production. Thus, once pDCs are activated they strongly promote the adaptive immune response. However, much less is known about the effects on pDCs by different adaptive immune cells. Therefore, we asked if T cells can promote the IFNα production by pDCs stimulated by RNA containing ICs.
Human T cells were activated by anti-CD3/CD28 antibodies. T cells or supernatant from T cell cultures were co-cultured with pDCs stimulated with ICs containing U1 snRNP particles and SLE-IgG (RNA-IC). Cells were analyzed by flow cytometry and cytokines in supernatants were depleted or blocked by monoclonal antibodies. Supernatants were analyzed for IFNα and other cytokines.
Activated T cells or supernatants from activated T cells increased the IFNα production by pDCs stimulated by RNA-IC >20-fold. The frequency of pDCs expressing intracellular IFNα increased when co-cultured with activated CD4+ T cells (5.8%) or CD8+ T cells (6.8%) compared to pDC cultured alone (0.2%). When cytokines were added to the RNA-IC stimulated pDCs at the same concentration as in the supernatant from activated T cells, both GM-CSF and IL-3 demonstrated a strong stimulatory effect on the IFNα response. The combination of both cytokines increased the IFNα production as much as supernatants from activated T cell. The stimulatory effect of supernatants was significantly reduced after depletion of GM-CSF (81%), blocking of GM-CSF (92%) or its receptor subunits CD131 and CD116 (55-81%), (all p<0.05). Blocking of IL-3 or its receptor subunit CD123 also reduced the stimulatory effect of the supernatant (31% and 32%, respectively). Supernatant from activated T cells increased the frequency of CD80 and CD86 expressing pDC from 6% to 35% (p<0.05) and 10% to 26% (p<0.01), respectively. Furthermore, when RNA-IC was added to pDCs cultured with GM-CSF and IL-3, an increased frequency of CD80 and CD86 (p<0.05) expressing pDCs were observed. Activated SLE T cells enhanced the IFNα production to the same extent as T cells from healthy controls. Detectable levels of serum-GM-CSF was found in 31% of SLE patients (n=51), who had a more active or severe disease.
Activated T cells enhance the IFNα production by RNA-IC stimulated pDCs via GM-CSF and IL-3, which induce maturation of the pDCs. Previous findings of activated T cells in patients with SLE and our observation of a subset of SLE patients expressing increased levels of serum-GM-CSF suggests that T cells contribute to the activated type I interferon system in SLE. Thus, a bidirectional crosstalk between the type I IFN system and the adaptive immune system seems to exist in SLE.
M. L. Eloranta,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/activated-sle-t-cells-enhance-the-interferon-alpha-production-by-plasmacytoid-dendritic-cells-stimulated-by-rna-ic/