Toll-like receptor 2 induced cytotoxic T-lymphocyte-associated protein 4 regulates Aspergillus-induced regulatory T-cells with pro-inflammatory characteristics

• Published in: Scientific reports 2017-09, Vol.7 (1), p.11500-9, Article 11500
• Main Authors: Raijmakers, Ruud P. H., Sprenkeler, Evelien G. G., Aleva, Floor E., Jacobs, Cor W. M., Kanneganti, Thirumala-Devi, Joosten, Leo A. B., van de Veerdonk, Frank L., Gresnigt, Mark S.
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 631/250/1619/554/1898/1271; 631/250/2152/569; 631/250/255/1672; 631/250/256; 631/326/193/2544; Aspergillosis; Aspergillus fumigatus; Asthma; Chronic obstructive pulmonary disease; CTLA-4 protein; Cystic fibrosis; Cytotoxicity; Fungal infections; Genotype & phenotype; Helper cells; Humanities and Social Sciences; Immune system; Immunocompromised hosts; Inflammation; Lung diseases; Lymphocytes; Lymphocytes T; multidisciplinary; Obstructive lung disease; Pulmonary lesions; Science; Science (multidisciplinary); Suppressor cells; T cell receptors; TLR2 protein; Toll-like receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-11738-4

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 (T H )2 and T H 17 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 T H 17-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 T H 17-like phenotype. We also demonstrate that these regulatory T-cells with a pro-inflammatory T H 17-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 T H 17-like phenotype in Aspergillus -associated immunopathology, and identifies key players, i.e. TLR2 and CTLA4, involved in this mechanism.