Identification of a New Phenotype of Tolerogenic Human Dendritic Cells Induced by Fungal Proteases from Aspergillus oryzae

The Journal of Immunology: Official Journal of the American Association of Immunologists

Emmanuel Nony¹  Philippe Moingeon¹  Laurence Van Overtvelt¹  Sonia Luce¹  Armelle Biola-Vidamment¹  Fanny Gaignier²  Marc Pallardy²  Aline Zimmer²  Laurent Mascarell²  Marie Naveau² 

[1]and

[2]Stallergènes, Antony Cedex 92183, France

[3]Universud, INSERM Unité Mixte de Recherche 996, Faculté de Pharmacie, Université Paris Sud 11, 92296 Chatenay-Malabry, France

DOI  :  10.4049/jimmunol.1003184

学科分类：生物科学（综合）

来源: American Association of Immunologists

【 摘 要 】

We characterized a new pathway to induce tolerogenic dendritic cells (DCs) following treatment of human monocyte-derived DCs with proteases from the fungus Aspergillus oryzae (ASP). ASP-treated DCs (ASP-DCs) exhibit a CD80−CD83−CD86−Ig-like transcript (ILT)2−ILT3−ILT4+ phenotype, do not secrete cytokines or chemokines, and express tolerogenic markers such as glucocorticoid-induced leucine zipper, NO synthetase-2, retinaldehyde dehydrogenase-1 or retinaldehyde dehydrogenase-2. When cocultured with naive CD4+ T cells, ASP-DCs induce an anergic state that can be reversed by IL-2. Generated T cells mediate a suppressive activity in third-party experiments that is not mediated by soluble factors. A comparison between dexamethasone-treated DCs used as a reference for regulatory T cell-inducing DCs and ASP-DCs reveals two distinct phenotypes. In contrast to dexamethasone, ASP treatment induces glucocorticoid-induced leucine zipper independently of glucocorticoid receptor engagement and leads to NF-κB p65 degradation. Abrogation of protease activities in ASP using specific inhibitors reveals that aspartic acid-containing proteases are key inducers of regulatory genes, whereas serine, cysteine, and metalloproteases contribute to NF-κB p65 degradation. Collectively, those features correspond to a previously unreported anergizing phenotype for human DCs. Such regulatory mechanisms may allow fungi to downregulate host immune responses and provide clues for new approaches to treat proinflammatory disorders.

【 授权许可】

CC BY