Type I IFN‐mediated Inhibition of Inflammatory Th cell Responses by a Subset of SLE Patient Sera

Abstract

Inflammatory, IFN‐γ‐secreting Th1 cells are implicated in mediating serious forms of systemic lupus erythematosus (SLE), including nephritis and CNS lupus. In SLE, triggering of plasmacytoid DC (pDC) Toll‐like receptors (TLRs) by circulating anti‐nucleic acid‐containing autoimmune complexes stimulates pDC secretion of high levels of type I interferon (IFN) (IFN‐α/β). Study of both human and murine lupus disease strongly implicates these IFNs as key disease effectors. However, the role of pDC‐derived type I IFN in regulating the function of inflammatory Th cells in SLE is unknown. We and others have shown that, although classically considered to promote Th1 cell mediated inflammation, type I IFN can also function as a potent inhibitor of both inflammatory Th1 and Th17 responses. We employed the pan‐type I IFN neutralizing reagent, B18R, to investigate how type I IFN regulate Th cell responses in SLE. Recent observations indicate a subset of SLE patient sera that inhibits IFN‐γ secretion by superantigen‐stimulated healthy donor PBMC in a type I IFN‐dependent manner. This effect positively correlates with PBMC secretion of the Th cell inflammatory cytokines, LT and IL‐17, while negatively correlating with IL‐10 secretion. Remarkably, the ability of SLE patient serum to inhibit IFN‐γ secretion in a type I IFN dependent manner correlates with positive serum Sm and RNP titers. Our findings suggest that in SLE patients with significant serum type I IFN activity, type I IFN blockade may exacerbate Th cell‐mediated autoimmune inflammation.