Healthy Human T-Cell Responses to Aspergillus fumigatus Antigens

Abstract

Background Aspergillus fumigatus is associated with both invasive and allergic pulmonary diseases, in different hosts. The organism is inhaled as a spore, which, if not cleared from the airway, germinates into hyphal morphotypes that are responsible for tissue invasion and resultant inflammation. Hyphae secrete multiple products that function as antigens, evoking both a protective (TH1–TH17) and destructive allergic (TH2) immunity. How Aspergillus allergens (Asp f proteins) participate in the development of allergic sensitization is unknown.Methodology/Principal FindingsTo determine whether Asp f proteins are strictly associated with TH2 responses, or represent soluble hyphal products recognized by healthy hosts, human T cell responses to crude and recombinant products were characterized by ELISPOT. While responses (number of spots producing IFN-γ, IL-4 or IL-17) to crude hyphal antigen preparations were weak, responses to recombinant Asp f proteins were higher. Recombinant allergens stimulated cells to produce IFN-γ more so than IL-4 or IL-17. Volunteers exhibited a diverse CD4+ and CD8+ T cell antigen recognition profile, with prominent CD4 TH1-responses to Asp f3 (a putative peroxismal membrane protein), Asp f9/16 (cell wall glucanase), Asp f11 (cyclophilin type peptidyl-prolyl isomerase) and Asp f22 (enolase). Strong IFN-γ responses were reproduced in most subjects tested over 6 month intervals.ConclusionsProducts secreted after conidial germination into hyphae are differentially recognized by protective T cells in healthy, non-atopic individuals. Defining the specificity of the human T cell repertoire, and identifying factors that govern early responses may allow for development of novel diagnostics and therapeutics for both invasive and allergic Aspergillus diseases.

Sensing of mammalian IL-17A regulates fungal adaptation and virulence

“…Although it was previously recognized that IFN-γ inhibits yeast-to-hyphal transition in C. albicans 14 , little progress had been made on the mechanistic details of this early observation. Our data show that a conserved family of GPI-anchored crosslinking enzymes, highly conserved in Candida and Aspergillus, and known to be exposed at growing sites-such as bud emergences or hyphal tips 22,23 -and detectable in mice 28,30,31 as well as in humans 32 , mediates IL-17A sensing by fungi. Thus, in addition to their involvement in adhesion and virulence 6,12 , these proteins are immunologically reactive.…”

Induction of A. fumigatus-specific CD4-positive T cells in patients recovering from invasive aspergillosis

“…In previous studies low frequencies of Aspergillus-specific T cells were identified in the peripheral blood of healthy individuals stimulated with conidia of A. fumigatus, 5,7,10 A. fumigatus crude extract, 5,8,10 A. fumigatus recombinant proteins 5,7,8 or overlapping peptides of A. fumigatus proteins.…”

“…6 In healthy individuals the presence of Aspergillus-specific T cells in peripheral blood was demonstrated by stimulating peripheral blood mononuclear cells (PBMC) with Aspergillus crude extracts or conidia, A. fumigatus recombinant proteins or overlapping peptides of A. fumigatus proteins. 5,[7][8][9][10][11][12][13] We have previously identified Crf1-and Catalase1-specific T cells in healthy individuals using overlapping peptides. Crf1-and Catalase1-specific T cells recognizing a broad variety of T-cell epitopes were identified in the majority of healthy individuals and Aspergillus reactivity was shown by stimulating the T cells with Aspergillus protein extract or recombinant protein.…”

Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease

“…In contrast to the protective immune response exemplified by Th1 and Th17 cells [132], Th2 effector cells are considered deleterious in lung fungal infections, in part because they dampen the protective Th1-cell responses. The detrimental Th2 Eur.…”