Periodic Reporting for period 5 - Baby DCs (Age-dependent Regulation of Dendritic Cell Development and Function)
Okres sprawozdawczy: 2023-06-01 do 2024-12-31
Early life immune balance is essential for survival and establishment of healthy immunity in later life. This project aims to define how age-dependent regulation of dendritic cell (DC) development contributes to this crucial immune balance. DCs are versatile controllers of immunity that in neonates are qualitatively distinct from adults. Why such age-dependent differences exist is unclear but newborn DCs are considered underdeveloped and functionally immature. In this project, we investigate the origins of the DC compartment with age. We will then define to what extent cellular origin determines age-dependent functions of DCs in immunity and investigate cell intrinsic and extrinsic mechanisms regulating the age-dependent functions of DCs. Because environmental factors in utero and after birth critically influence immune balance, we will finally define the impact of maternal infection and metabolic disease, as well as early microbial encounter on DC poiesis. Characterizing how developmentally regulated DC poiesis shapes the unique features of early life immunity will provide novel insights into immune development that are vital to advance vaccine strategies.
Conventional dendritic cells (cDCs) are versatile controllers of immunity that exist as developmentally distinct subsets, so called cDC1 and cDC2, with distinct ability to prime T cells. Here, we have identified a previously unrecognized heterogeneity of the cDC2 compartment in early life mouse spleen. Surprisingly, ontogenetically distinct cDC2 are phenotypically, functionally and transcriptionally similar. Importantly, early life cDC2 can activate naive T cells and support effector differentiation better than adult cDC2. Splenic cDC2 further show age-dependent differences in gene expression that indicate that early life cDC2 are not functionally immature but equipped with a transcriptional machinery that alters their ability to sense pathogens and induce immune responses. Our demonstration that early life cDC2 are fully capable of initiating naïve CD4 T cell activation and Th17 differentiation highlights the potential of harnessing these cells for boosting protective immunity. Importantly, we show that environmental signals, rather than cell intrinsic mechanisms imprint the functions of cDC2 but also cDC1 across age. We further show that dendritic cells carefully integrate integrate homeostatic tissue-derived signals to regulate immune development, either promoting tolerance or preparing for immune defense. This regulation appears in part independent of the microbiota. This work opens new doors to boost vaccine efficiency in early life.
Further, we have unexpectedly identified a unique population of dendritic cells that are marked by expression of the transcription factor RORγt – so-called RORγt+ dendritic cells (DCs). These cells are found in many tissues and have been conserved across many species in the course of evolution. Under normal conditions, RORγt+ DCs help prevent the immune system from attacking harmless things, like our gut bacteria or food components. But in times of infection or inflammation, they can switch roles and activate other immune cells. Of particular interest, is the demonstration that these cells also appear to be involved in diseases like multiple sclerosis. In patients with multiple sclerosis, they take on an aggressive profile, suggesting they contribute to inflammation in the brain and spinal cord. The dual functionality of RORγt+ DCs also opens the door to new treatment possibilities. For example, the cells could be targeted either to calm down an overactive immune system or to boost the immune system.
Further, we have unexpectedly identified a unique population of dendritic cells that are marked by expression of the transcription factor RORγt – so-called RORγt+ dendritic cells (DCs). These cells are found in many tissues and have been conserved across many species in the course of evolution. Under normal conditions, RORγt+ DCs help prevent the immune system from attacking harmless things, like our gut bacteria or food components. But in times of infection or inflammation, they can switch roles and activate other immune cells. Of particular interest, is the demonstration that these cells also appear to be involved in diseases like multiple sclerosis. In patients with multiple sclerosis, they take on an aggressive profile, suggesting they contribute to inflammation in the brain and spinal cord. The dual functionality of RORγt+ DCs also opens the door to new treatment possibilities. For example, the cells could be targeted either to calm down an overactive immune system or to boost the immune system.
Neonates are highly susceptible to infections with pathogens such as Candida albicans, Bordetella pertussis and Streptococcus pneumoniae, which can cause life-threatening complications in early life. Protective immune responses against these pathogens require T helper 17 priming that are predominantly iniated by cDC2. Our demonstration that early life cDC2 are fully capable of initiating naïve CD4 T cell activation and Th17 differentiation highlights the potential of harnessing these cells for boosting protective immunity. We are currently investigating whether targeting antigen specifically to these cells can induce protective immune responses in early life. Studies are also currently under way to investigate the cell intrinsic and extrinsic factors that regulate dendritic cell function with age. Our discovery of RORγt⁺ dendritic cells (DCs) reveals their dual role in maintaining immune tolerance under normal conditions while driving inflammation in diseases like multiple sclerosis, where they adopt a pro-inflammatory profile in the brain and spinal cord. This unique functionality presents new therapeutic opportunities, where selectively targeting RORγt⁺ DCs could either suppress autoimmune inflammation or enhance immune responses in a disease-specific manner.