Regulation of human dendritic cell activation

Division Of Basic Sciences - Nci

Investigators

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Abstract

The effort on this project due to limitation of resources largely shifted to studies in mice on the role of hematopietic cells and myeloid cells in particular in regulating immune functions, particularly related to the role of the microbiome in cancer immunity. Because of this change in focus merging to other projects and the limitation of resources, in the next year this project will be discontinued and merged in the two other main projects in the Section. Oral fungal infection impacts epithelial innate immunity to promote local and distal tumor growth by affecting myeloid cell activation: In mice that lack epithelial expression of the immune protein IKK alpha, oral infection with the Cladosporium cladosporioides fungi increases their colonization and development of both oral and skin squamous cell carcinoma (SCC). Fungal-induced intratumoral STAT3 signaling generates acidic metabolites in the oral cavity that repress the antifungal phagocytic activity of neutrophils and, in conjunction with skin macrophages, increase IL-1b-inflammatory signature. Oral fungal infection also induces systemic IL-1b/IL-17A that enhance skin carcinogenesis. Consistently, advanced human head and neck SCCs that are infiltrated by neutrophils expressing High-IL1B/Low-phagocytic signatures have been found to be colonized by fungi. Collectively our findings reveal novel mechanisms of cooperation between epithelial and innate immune cells leading to resistance to both fungal infection and cancer development. The manuscript describing these findings is under revision. The gut microbiome controls liver tumors via the vagus nerve: Nerves have emerged as an understudied regulator of tumor progression. The parasympathetic vagus nerve influences systemic immunity via acetylcholine (ACh). Whether cholinergic neuroimmune interactions influence hepatocellular carcinoma (HCC) remains uncertain. Liver denervation via hepatic vagotomy (HV) significantly reduced liver tumor burden, while pharmacological enhancement of parasympathetic tone promoted tumor growth. Cholinergic disruption in Rag1KO mice revealed that cholinergic regulation requires adaptive immunity. Further scRNA-seq and in vitro studies indicated that vagal ACh dampens CD8+ T cell activity via muscarinic ACh receptor (AChR) CHRM3. Depletion of CD8+ T cells abrogated HV outcomes and selective deletion of Chrm3 on CD8+ T cells inhibited liver tumor growth. Beyond tumor-specific outcomes, vagotomy improved cancer associated fatigue and anxiety-like behavior. As microbiota transplantation from HCC donors was sufficient to impair behavior, we investigated putative microbiota-neuroimmune crosstalk. Tumor, rather than vagotomy, robustly altered fecal bacterial composition, incre associated microbiota to activate hepatic CD8+ T cells. These findings reveal that gut bacteria influence behavior and liver anti-tumor immunity via a dynamic and pharmaceutically targetable, vagus-liver axis. The manuscript describing these studies, previously in part reported in a deposited preprint in BioArchives, has been submitted and it is under revision. Chaotic dynamics for homeostatic hematopoiesis: Hematopoiesis is a highly dynamical and stochastic process. Clinical studies of leukemia or neutropenic patients revealed that multiple blood cell types fluctuate spontaneously with large yet regular oscillations of their frequencies. Here we report on both cross-sectional and longitudinal studies of dozens of healthy mice, through high-dimensional mass and spectral cytometry, to understand hematopoiesis at homeostasis. We found that all cell types in the bone marrow, blood, and spleen exhibit large variations of frequency (e.g., with coefficients of variation larger than 1). While the frequencies of individual cell type fluctuate, there existed extensive and robust correlations/anti-correlations between cell types, exemplified by the pronounced anti-correlation between blood neutrophils and B cells. Through longitudinal study of the blood content of healthy mice, we found that leukocyte fluctuations are ergodic yet subject to chaotic behaviors characterized by a broad spectrum of characteristic timescales. We then built a minimal mathematical model to capture these dynamical features of hematopoiesis (fluctuations, correlations, and chaos) and explain how the accumulation of B cells (e.g. during lymphoma development) would transition the blood cell dynamics from chaos to oscillations (as observed clinically). Finally, we demonstrated the ubiquity and consistency of the correlated fluctuations in hematopoiesis by comparing mouse cohorts of different genetic backgrounds and ages. The manuscript describing these studies, previously in part reported in a deposited preprint in BioArchives, has been submitted and it is under revision.