title: Aspergillus fumigatus-induced IL-22 is not restricted to a specific Th cell subset and is dependent on complement receptor 3.
abstract: Th cell responses induced by Aspergillus fumigatus have been extensively investigated in mouse models. However, the requirements for differentiation and the characteristics of A. fumigatus-induced human Th cell subsets remain poorly defined. We demonstrate that A. fumigatus induces Th1 and Th17 subsets in human PBMCs. Moreover, we show that the cytokine IL-22 is not restricted to a specific Th subset, in contrast to IL-17A. The pattern recognition and cytokine pathways that skew these Aspergillus-induced Th cell responses are TLR4- and IL-1-, IL-23-, and TNF-α-dependent. These pathways are of specific importance for production of the cytokines IL-17A and IL-22. Additionally, our data reveal that the dectin-1/Syk pathway is redundant and that TLR2 has an inhibitory effect on Aspergillus-induced IL-17A and IL-22 production. Notably, blocking complement receptor (CR)3 significantly reduced Aspergillus-induced Th1 and Th17 responses, and this was independent on the activation of the complement system. CR3 is a known receptor for β-1,3-glucan; however, blocking CR3 had significant effects on Th cell responses induced by heat-killed Aspergillus conidia, which have minimal β-glucan expression on their cell surface. Collectively, these data characterize the human Th cell subsets induced by Aspergillus, demonstrate that the capability to produce IL-22 is not restricted to a specific T cell subset, and provide evidence that CR3 might play a significant role in the adaptive host defense against Aspergillus, although the ligand and its action remain to be elucidated.
authors: Department of Medicine, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands.
authors: Mark S
authors: MS
authors: Gresnigt
authors: Katharina L
authors: KL
authors: Becker
authors: Sanne P
authors: SP
authors: Smeekens
authors: Cor W M
authors: CW
authors: Jacobs
authors: Leo A B
authors: LA
authors: Joosten
authors: Jos W M
authors: JW
authors: van der Meer
authors: Mihai G
authors: MG
authors: Netea
authors: Frank L
authors: FL
authors: van de Veerdonk
mesh_terms: D001232:Aspergillus fumigatus / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D000097043:Interleukin-22; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D011951:Receptors, Complement; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000097043:Interleukin-22; C546929:CLEC7A protein, human; D000099181:Dectin-1; C000606896:SYK protein, human; C000606897:Syk protein, mouse