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.
