Abstract
IFN‐γ‐producing T helper 1 (Th1) cell responses mediate protection against infections but uncontrolled Th1 activity also contributes to a broad range of autoimmune diseases. Autocrine complement activation has recently emerged as key in the induction and contraction of human Th1 immunity: activation of the complement regulator CD46 and the C3aR expressed by CD4+ T cells via autocrine generated ligands C3b and C3a, respectively, are critical to IFN‐γ production. Further, CD46‐mediated signals also induce co‐expression of immunosuppressive IL‐10 in Th1 cells and transition into a (self)‐regulating and contracting phase. In consequence, C3 or CD46‐deficient patients suffer from recurrent infections while dysregulation of CD46 signaling contributes to Th1 hyperactivity in rheumatoid arthritis and multiple sclerosis. Here, we report a defect in CD46‐regulated Th1 contraction in patients with systemic lupus erythematosus (SLE). We observed that MMP‐9‐mediated increased shedding of soluble CD46 by Th1 cells was associated with this defect and that inhibition of MMP‐9 activity normalized release of soluble CD46 and restored Th1 contraction in patients’ T cells. These data may deliver the first mechanistic explanation for the increased serum CD46 levels observed in SLE patients and indicate that targeting CD46‐cleaving proteases could be a novel avenue to modulate Th1 responses.
Highlights
Systemic lupus erythematosus (SLE) is a complex autoimmune disease of uncertain etiology [1]
To assess if perturbation in the complement-CD46-driven pathways contribute to dysregulated T helper 1 (Th1) responses observed in SLE, we activated this pathway in purified CD4+ T cells from healthy controls (HCs) and individuals with SLE and measured active IFN-γ and IL-10 secretion
CD46mediated signals were required for normal Th1, but not Th2 responses, because the IL-4 and IL-5 levels were unaltered in SLE T cells after CD3+CD46 activation (Fig. 1D) or after CD3 and CD3+CD28 stimulation
Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease of uncertain etiology [1]. One hallmark of SLE is dysregulated cytokine production, which contributes to immune dysfunction and tissue inflammation [2]. Type I and II interferons (IFN) [3] have been implicated in SLE induction and progression. Much emphasis has been placed on type I IFNs [4],. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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