Department of Experimental Internal Medicine and Radboud Center for Infectious diseases (RCI), Radboud University Medical Center, Geert Grooteplein zuid 8, 6525GA, Nijmegen, The Netherlands.
Department of Respiratory Medicine, Radboud University Medical Center, Geert Grooteplein zuid 10, 6525 GA, Nijmegen, The Netherlands.
Sci Rep. 2017 Sep 13;7(1):11500. 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)2 and T17 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 T17-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 T17-like phenotype. We also demonstrate that these regulatory T-cells with a pro-inflammatory T17-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 T17-like phenotype in Aspergillus-associated immunopathology, and identifies key players, i.e. TLR2 and CTLA4, involved in this mechanism.
患有囊胞性纤维症、慢性阻塞性肺病、严重气喘、先前存在肺部损伤以及严重免疫功能低下的患者易受机会性致病真菌烟曲霉感染，即曲霉菌病。这些患者的感染与持续的促炎辅助性 T 细胞（T helper，Th）2 和 Th17 反应有关。调节性 T 细胞是免疫系统的天然抑制细胞，可控制促炎 T 细胞反应，但也可通过向促炎 Th17 样表型转变而促进疾病发生。这种转变可能在曲霉菌病中所见的有害免疫病理中发挥重要作用。我们的研究表明，烟曲霉可诱导具有 Th17 样表型的调节性 T 细胞。我们还表明，通过激活调节细胞毒性 T 淋巴细胞相关蛋白 4（cytotoxic T-lymphocyte-associated protein 4，CTLA4）诱导的 Toll 样受体 2（Toll-like receptor 2，TLR2），可将具有促炎 Th17 样表型的这些调节性 T 细胞重新编程为其“经典”抗炎表型。同样，可溶性 CTLA4 可逆转烟曲霉诱导的调节性 T 细胞的促炎表型。总之，我们的结果表明，具有促炎 Th17 样表型的调节性 T 细胞在曲霉菌相关免疫病理学中发挥作用，并确定了参与该机制的关键因子，即 TLR2 和 CTLA4。
