Toll-like receptor\xa02 induced cytotoxic T-lymphocyte-associated protein\xa04 regulates Aspergillus-induced regulatory T-cells with pro-inflammatory characteristics

Ruud P H Raijmakers,Floor E Aleva,Mark S Gresnigt,Thirumala-Devi Kanneganti,Leo A B Joosten,Frank L Van De Veerdonk,Evelien G G Sprenkeler,Cor W M Jacobs

doi:10.1038/s41598-017-11738-4

Abstract

Patients with cystic fibrosis, chronic obstructive pulmonary disease, severe asthma, pre-existing pulmonary lesions, and severely immunocompromised patients are susceptible to develop infections with the opportunistic pathogenic fungus Aspergillus fumigatus, called aspergillosis. Infections in these patients are associated with persistent pro-inflammatory T-helper (TH)2 and TH17 responses. Regulatory T-cells, natural suppressor cells of the immune system, control pro-inflammatory T-cell responses, but can also contribute to disease by shifting to a pro-inflammatory TH17-like phenotype. Such a shift could play an important role in the detrimental immunopathology that is seen in aspergillosis. Our study demonstrates that Aspergillus fumigatus induces regulatory T-cells with a TH17-like phenotype. We also demonstrate that these regulatory T-cells with a pro-inflammatory TH17-like phenotype can be reprogrammed to their “classical” anti-inflammatory phenotype by activating Toll-like receptor 2 (TLR2), which regulates the induction of cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Similarly, soluble CTLA4 could reverse the pro-inflammatory phenotype of Aspergillus-induced regulatory T-cells. In conclusion, our results suggest a role for regulatory T-cells with a pro-inflammatory TH17-like phenotype in Aspergillus-associated immunopathology, and identifies key players, i.e. TLR2 and CTLA4, involved in this mechanism.

Highlights

Opportunistic infections caused by Aspergillus fumigatus are frequently observed in immunocompromised patients
By determining the kinetics of IL-17A and IL-10 production over a course of 7 days in peripheral blood mononuclear cells (PBMCs) simulated with A. fumigatus conidia, we determined the optimal time point to detect TH17-like pro-inflammatory Treg cells
In this study we investigated whether A. fumigatus-induced Treg cells exert a pro-inflammatory phenotype, and if this pro-inflammatory phenotype can be reprogrammed to the “classical” anti-inflammatory Treg phenotype

Summary

Introduction

Opportunistic infections caused by Aspergillus fumigatus are frequently observed in immunocompromised patients. Other patient groups at risk of developing disease caused by A. fumigatus are patients with cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), severe asthma, or individuals with pre-existing pulmonary lesions[2,3,4,5,6] Clinical manifestations of such disease are called (invasive) aspergillosis, and range from hypersensitivity reactions to A. fumigatus, as is seen in allergic bronchopulmonary aspergillosis (ABPA)[5, 7], to insufficient clearance of A. fumigatus with long-lasting inflammatory responses and ongoing fungal growth, as is seen in chronic pulmonary aspergillosis (CPA)[2, 3]. Several studies demonstrated that Treg cells can acquire pro-inflammatory characteristics by differentiating into Interleukin (IL)-17A producing RAR-related orphan receptor γt (RORγt) expressing T-cells[22, 23] This conversion was found to be involved in the pathogenesis of autoimmune arthritis and depends on pro-inflammatory cytokines such as IL-2 and IL-1523. Such a shift could play a crucial role in the IL-17 mediated immunopathology that is seen in patients with aspergillosis

Methods

Results

Conclusion