Jintao Xu, PhD

Life-threatening invasive fungal infections affect millions of people worldwide annually. Current treatments are ineffective and toxic; thus, we need to understand how our bodies defend against fungal infections for new therapeutics like immunotherapies and vaccines. My study focuses on dendritic cells (DC). They are one of the most important cell types to be studied in the context of designing effective immunotherapies and vaccines because these cells uniquely shape how our body responds to infections. Intriguingly, DC are diverse and show a division of labor in their functions between different populations. However, understanding of such DC division of labor during fungal infections is extremely limited. Uncovering the functions of the lung DC subset is essential for rationally designing immunotherapies and vaccines against fungal lung infections. DC subsets often share common traits and constantly acquire new characteristics over the infection; thus, it is challenging to precisely separate them and study their functions. Here, we used cutting-edge flow cytometry and single-cell technologies to uncover the specific function of each DC subset and their pathways in shaping lung anti-fungal immune responses. In a mouse model, we used newly identified cell markers to precisely distinguish different DC subsets, including monocyte-derived DC, type 1 conventional DC, type 2 conventional DC, and inf-cDC2. Previous studies suggested that monocyte-derived DC were vital for promoting protective anti-fungal immunity. Unexpectedly, our study challenges this idea using more reliable cell markers and shows that this population of DC does not present in the lung draining lymph nodes, where programming of protective immunity occurs. Instead, our studies showed that inf-cDC2 migrate into the lung draining lymph nodes and can optimally induce protective immunity against fungal infections. In summary, we have discovered new functional specializations of DC subsets and dissected the mechanisms employed by DC subsets in modulating anti-fungal immunity. Our findings thus can be used to guide the process of developing new immune-based therapies and vaccines for patients affected by pulmonary fungal diseases.

Update: Fungal infections in the lungs cause life-threatening diseases despite currently available treatments. There is an urgent need to understand host defenses against fatal mycoses for novel therapeutics like immunotherapies and vaccines. Dendritic cells uniquely shape host anti-fungal immunity. However, those cells in the lungs are diverse, and our understanding of their division of labor in lung fungal infections is extremely limited. We used cutting-edge flow cytometry and single-cell technologies to uncover the specific function of each subset and their pathways in mediating lung anti-fungal immune responses. We discovered that inf-cDC2s, a newly identified DC subset, can optimally initiate protective T cell responses during fungal infections in the lung draining lymph nodes. Pathways discovered in this study can be explored as supportive immune therapies for patients with lung fungal infections.