Journal
FRONTIERS IN IMMUNOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.02449
Keywords
complement; CD46; T cell; cathepsin L; AEP; legumain
Categories
Funding
- MRC Centre [MR/J006742/1]
- Wellcome Trust Investigator Award
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London
- Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH
- MRC [G1002165] Funding Source: UKRI
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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-gamma 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 alpha 1-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-gamma 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-gamma secretion and Th1 induction. Furthermore, we did not observe a role for AEP-driven autocrine alpha 1-thymosin activation in T cell-derived IFN-gamma production. These data suggest that AEP is an upstream activator of the CTSL-C3-IFN-gamma axis in human CD4(+) T cells and hence an important supporter of human Th1 induction.
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