Dysregulated CD46 shedding interferes with Th1-contraction in systemic lupus erythematosus

Ursula Ellinghaus, Andrea Cortini, Christopher L. Pinder, Gaelle Le Friec, Claudia Kemper*, Timothy J. Vyse

*Corresponding author for this work
21 Citations (Scopus)


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.

Original languageEnglish
JournalEuropean Journal of Immunology
Issue number7
Pages (from-to)1200-1210
Number of pages11
Publication statusPublished - 07.2017

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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