Dendritic cells heterogeneity and function

National Institute Of Dental & Craniofacial Research

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Abstract

Our research has highlighted the intrinsic and extrinsic cues that determine developmental trajectories of hematopoietic stem cells (HSCs) towards erythroid, myeloid and lymphoid lineages. We generated two novel transgenic mice that report and trace the expression of the enzyme terminal deoxynucleotidyl transferase (TdT). This enzyme inserts random nucleotides at the joining regions of T and B cell receptor, thereby increasing the variability of antibodies and T cell receptors. This ensures that immunity towards any potential pathogen is effective and specific. In these mice models we saw transient induction of TdT on a newly identified multipotent progenitor (MPP) subset that lacked self-renewal capacity but maintained multilineage differentiation potential. Further, TdT induction on MPPs reflected a transcriptionally dynamic but uncommitted stage, characterized by low expression of lineage-associated genes. This transcriptional state allows for multiple developmental options to be maintained open. Single-cell CITE-sequencing indicated that multipotency in the TdT+ MPPs is associated with expression of the endothelial cell adhesion molecule ESAM. Stable and progressive upregulation of TdT defined the lymphoid developmental trajectory. While downregulation of this gene resulted in alternative developmental options. Collectively, we could identify a new multipotent progenitor within the MPP4 compartment. Specification and commitment are defined by downregulation of ESAM which marks the progressive loss of alternative fates along all lineages. Dissecting each precursor stage will allow us to determine the specific transcriptional programs that allow for hematopoietic lineege development.