Wiesner Darin L, Specht Charles A, Lee Chrono K, Smith Kyle D, Mukaremera Liliane, Lee S Thera, Lee Chun G, Elias Jack A, Nielsen Judith N, Boulware David R, Bohjanen Paul R, Jenkins Marc K, Levitz Stuart M, Nielsen Kirsten
Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
PLoS Pathog. 2015 Mar 12;11(3):e1004701. doi: 10.1371/journal.ppat.1004701. eCollection 2015 Mar.
Pulmonary mycoses are often associated with type-2 helper T (Th2) cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection.
肺部真菌病常与2型辅助性T（Th2）细胞反应相关。然而，Th2细胞积累的机制是多因素的，且尚未完全明确。为了研究Th2细胞对肺部真菌感染的反应，我们开发了一种肽-MHCII四聚体来追踪针对真菌病原体新型隐球菌感染产生的抗原特异性CD4+ T细胞。我们注意到感染后肺部出现大量病理性新型隐球菌抗原特异性Th2细胞，这是由肺驻留的CD11b+ IRF4依赖性传统树突状细胞协调的。其他研究人员已经证明，这个树突状细胞亚群也能够启动对另一种肺部真菌感染——烟曲霉的保护性Th17细胞反应。因此，这些树突状细胞对真菌感染特定特征的高阶检测必定指导Th2细胞谱系分化。由于含几丁质的寄生虫通常引发Th2反应，我们推测对真菌几丁质的识别是Th2细胞介导的真菌病的一个重要决定因素。使用新型隐球菌突变体或纯化的几丁质，我们发现几丁质丰度影响Th2细胞积累和疾病。重要的是，我们确定Th2细胞的诱导依赖于通过哺乳动物几丁质酶——壳三糖苷酶对几丁质的裂解，这种酶在患有明显隐球菌病的人类中也很普遍。本文提供的数据为真菌病易感性提供了一个新视角，即通过壳三糖苷酶识别几丁质会导致CD11b+传统树突状细胞在肺部真菌感染时启动有害的Th2细胞分化。
