Xu Jintao, Hissong Rylan, Bareis Rachel, Creech Arianna, Goughenour Kristie D, Freeman Christine M, Olszewski Michal A
Research Service, Department of Veterans Affairs Health System, Ann Arbor VA Health System, Ann Arbor, Michigan, USA.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA.
mBio. 2024 Mar 13;15(3):e0285323. doi: 10.1128/mbio.02853-23. Epub 2024 Feb 13.
While type I conventional dendritic cells (cDC1s) are vital for generating adaptive immunity against intracellular pathogens and tumors, their role in defense against fungal pathogen remains unclear. We investigated the role of the cDC1 subset in a fungus-restricting mouse model of cryptococcal infection. The cDC1 subset displayed a unique transcriptional signature with highly upregulated T-cell recruitment, polarization, and activation pathways compared to other DC subsets. Using Batf3 mice, which lack the cDC1 population, our results support that Batf3-dependent cDC1s are pivotal for the development of the effective immune response against cryptococcal infection, particularly within the lung and brain. Deficiency in Batf3 cDC1 led to diminished CD4 accumulation and decreased IFNγ production across multiple organs, supporting that cDC1s are a major driver of potent Th1 responses during cryptococcal infection. Consistently, mice lacking Batf3-cDC1 demonstrated markedly diminished fungicidal activity and weaker containment of the fungal pathogen. In conclusion, Batf3-dependent cDC1 can function as a linchpin in mounting Th1 response, ensuring effective fungal control during cryptococcal infection. Harnessing cDC1 pathways may present a promising strategy for interventions against this pathogen.IMPORTANCE causes severe meningoencephalitis, accounting for an estimated 200,000 deaths each year. Central to mounting an effective defense against these infections is T-cell-mediated immunity, which is orchestrated by dendritic cells (DCs). The knowledge about the role of specific DC subsets in shaping anti-cryptococcal immunity is limited. Here, we demonstrate that Batf3 cDC1s are important drivers of protective Th1 CD4 T-cell responses required for clearance of cryptococcal infection. Deficiency of Batf3 cDC1 in the infected mice leads to significantly reduced Th1 response and exacerbated fungal growth to the point where depleting the remaining CD4 T cells no longer affects fungal burden. Unveiling this pivotal role of cDC1 in antifungal defense is likely to be important for the development of vaccines and therapies against life-threatening fungal pathogens.
虽然I型传统树突状细胞（cDC1s）对于产生针对细胞内病原体和肿瘤的适应性免疫至关重要，但其在抵御真菌病原体方面的作用仍不清楚。我们在一个限制真菌的新型隐球菌感染小鼠模型中研究了cDC1亚群的作用。与其他树突状细胞亚群相比，cDC1亚群表现出独特的转录特征，其T细胞募集、极化和激活途径高度上调。使用缺乏cDC1群体的Batf3小鼠，我们的结果支持依赖Batf3的cDC1s对于针对新型隐球菌感染的有效免疫反应的发展至关重要，尤其是在肺和脑内。Batf3 cDC1的缺陷导致多个器官中CD4积累减少和IFNγ产生降低，支持cDC1s是新型隐球菌感染期间强效Th1反应的主要驱动因素。一致地，缺乏Batf3-cDC1的小鼠表现出明显减弱的杀真菌活性和对真菌病原体的较弱控制。总之，依赖Batf3的cDC1可以作为启动Th1反应的关键因素，确保在新型隐球菌感染期间有效控制真菌。利用cDC1途径可能是针对这种病原体进行干预的一种有前景的策略。重要性新型隐球菌导致严重的脑膜脑炎，估计每年造成20万人死亡。对这些感染进行有效防御的核心是T细胞介导的免疫，这是由树突状细胞（DCs）精心安排的。关于特定DC亚群在塑造抗新型隐球菌免疫中的作用的知识有限。在这里，我们证明Batf3 cDC1s是清除新型隐球菌感染所需的保护性Th1 CD4 T细胞反应的重要驱动因素。感染小鼠中Batf3 cDC1的缺陷导致Th1反应显著降低，真菌生长加剧，以至于耗尽剩余的CD4 T细胞不再影响真菌负荷。揭示cDC1在抗真菌防御中的这一关键作用可能对开发针对危及生命的真菌病原体的疫苗和疗法很重要。
