Asparaginyl endopeptidase (Legumain) supports human Th1 induction via cathepsin L-mediated intracellular C3 activation

Simon Freeley, John Cardone, Sira C. Günther, Erin E. West, Thomas Reinheckel, Colin Watts, Claudia Kemper, Martin V. Kolev

    Research output: Contribution to journalArticlepeer-review

    7 Citations (Scopus)
    154 Downloads (Pure)

    Abstract

    Autocrine activation of the complement receptors C3aR and CD46 by complement activation components C3a and C3b produced through C3 cleavage by the protease cathepsin L (CTSL) during T cell stimulation is a requirement for IFN-γ production and Th1 induction in human CD4+ T cells. Thus, lack of autocrine CD46 activation, such as in CD46-deficient patients, is associated with defective Th1 responses and recurrent infections. We have identified LGMN [the gene coding for legumain, also known as asparaginyl endopeptidase (AEP)] as one of the key genes induced by CD46 co-stimulation during human CD4+ T cell activation. AEP processes and activates a range of proteins, among those α1-thymosin and CTSL, which both drive intrinsically Th1 activity-but has so far not been described to be functionally active in human T cells. Here we found that pharmacological inhibition of AEP during activation of human CD4+ T cells reduced CTSL activation and the CTSL-mediated generation of intracellular C3a. This translated into a specific reduction of IFN-γ production without affecting cell proliferation or survival. In line with these findings, CD4+ T cells isolated from Lgmn-/- mice also displayed a specific defect in IFN-γ secretion and Th1 induction. Furthermore, we did not observe a role for AEP-driven autocrine α1-thymosin activation in T cell-derived IFN-γ production. These data suggest that AEP is an "upstream" activator of the CTSL-C3-IFN-γ axis in human CD4+ T cells and hence an important supporter of human Th1 induction.

    Original languageEnglish
    Article number2449
    Pages (from-to)1-7
    Number of pages7
    JournalFrontiers in Immunology
    Volume9
    DOIs
    Publication statusPublished - 24 Oct 2018

    Keywords

    • AEP
    • Cathepsin L
    • CD46
    • Complement
    • Legumain
    • T cell

    Fingerprint Dive into the research topics of 'Asparaginyl endopeptidase (Legumain) supports human Th1 induction via cathepsin L-mediated intracellular C3 activation'. Together they form a unique fingerprint.

    Cite this