Conserved and novel functions of conventional dendritic cells: an evolutionary approach

Objective

ZebraDC aims to establish the zebrafish as a tractable model for conventional dendritic cell (cDC) research and leverage its strengths to uncover conserved and non-canonical cDC functions across vertebrates. While mammalian cDCs are well defined into three subsets—cDC1, cDC2A, and cDC2B—emerging evidence suggests that these cells also engage in underexplored roles beyond adaptive immune priming, including interactions with the nervous system. By integrating comparative immunology, advanced imaging, gene editing, and transcriptomics across zebrafish, mouse, and human models, this proposal will: (1) define zebrafish dendritic cells at the transcriptional level and establish their bona fide identity as cDCs, (2) dissect their developmental origin and functional properties to align them with vertebrate counterparts, and (3) validate conserved non-canonical cDC functions that could reshape current paradigms in immunology. Preliminary data support the feasibility of this approach, including a novel zebrafish flt3 reporter line with high specificity for putative cDCs, enabling in vivo tracking and functional studies. By harnessing the unique experimental advantages of the zebrafish and complementing these findings with mammalian validation, this project will advance our understanding of the evolutionary foundations of cDC biology and redefine their functional landscape. Ultimately, it will provide critical insights into cDC-mediated regulation of immunity and beyond, with implications for vaccination, inflammation, cancer, and neuro-immune therapies.