Regulation of human plasmacytoid dendritic cells by inhibitors of interferon-alpha

• Applicant: Dr. Dorit Fabricius
• Subject Area: Immunology
• Term: from 2007 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 52793729

Plasmacytoid dendritic cells (pDC) are crucially involved in early immune responses. A better understanding of pDC regulation may improve immunotherapeutic approaches to cancer, infectious diseases and autoimmunity. During the last two years we explored 1) how prostaglandin E2 (PGE2) and PG analogs impact on IFN-α secretion by pDC from healthy and systemic lupus erythematosus (SLE) subjects and 2) we started characterizing our novel finding that pDC are a potent source of granzyme B (GrB). In the first part of our project we could show that PGE2 and analogs potently inhibit IFN-α secretion by pDC, a process mediated by PG receptors EP2 and EP4. Importantly, profound IFN-α inhibition by PGE2 was also seen in pDC from subjects with SLE. Our data suggest PGE2 and analogs should be evaluated as novel treatment option in patients with SLE and other IFN-α-associated autoimmune diseases. In the second part of our project we revealed that pDC effectively suppress T cell proliferation by secreting large amounts of the serine protease GrB. Importantly, IL-3 plays a key role for GrB induction and IL-10 enhances, while toll-likereceptor agonists and CD40 ligand inhibit GrB secretion. Since various inflammatory diseases are associated with elevated GrB levels, pDC may play an important and yet unrecognized immunoregulatory role in these diseases. We intend to continue elucidating in more detail the effects of further immunomodulators including the mTOR inhibitor rapamycin, the growth factors Flt3 ligand and VEGF, and the cytokine TGF-β on pDC IFN-α and GrB secretion. By including healthy subjects, a selection of autoimmune individuals and subjects before and after anti-viral vaccinations, we hope to achieve a better insight of the role of pDC in health and disease and how these potent immunomodulating cells may be manipulated therapeutically.

• DFG Programme: Research Grants