Assistant Professor of Microbiology & Immunology
Ph.D., Rockefeller University

Molecular regulation of dendritic cell development and function

Dendritic cells (DCs) are specialized antigen presenting cells (APCs) and essential mediators of tolerance and immunity. Conditional ablation of DCs leads to defects in protective T cell priming and memory maintenance against infection; while constitutive DC deficiency results in lympho- and myeloproliferative syndromes and autoimmunity.

Lymphoid organs contain subsets of DCs in distinct locations and with unique functions. Despite their differences, all classic DCs (cDCs) in these organs originate from precursors called pre-DCs that we recently defined. The Pre-DC stage is a critical step in the DC development process that consists of sequential progenitors. Downstream of hematopoietic stem cells, CMPs (Common Myeloid Progenitors) progress through MDPs (Macrophage and DC progenitors) to CDPs (Common DC Progenitors), the latter of which differentiate to committed pre-DCs in the bone marrow; Pre-DCs migrate through the blood, and seed peripheral tissues where they further differentiate into subsets of DCs with unique cell surface features and functions. This whole pathway is dependent on Flt3L (FMS-like receptor tyrosine kinase 3 ligand), a hematopoietin that acts primarily on the DC lineage. Two closely related myeloid lineages branch off along the DC developmental pathway in the bone marrow: the monocyte lineage diverges at the MDP stage, and the plasmacytoid DC (pDC) lineage splits at CDP stage. The mechanisms regulating lineage divergence remain unclear. Non-lymphoid organs also contain cDCs. For example, we have recently identified a cDC population at the "gates" to the central nervous system, and their development and functions are yet to be elucidated.

The capacity to monitor and isolate DCs and their precursors enables us to compare their gene expression profiles and select candidate molecules that regulate DC and monocyte development and function. With physiological methods and genetic tools we have developed, we are pursuing the following questions: 1) What are the molecular switches controlling the DC and monocyte lineage split in the bone marrow? 2) How do pre-DCs obtain cues in the peripheral tissues to differentiate into various DC subsets and maintain their special phenotype and function? and 3) How do DC development and homeostasis respond to immune perturbation such as viral infection and tumor?

The long-term goal of our studies is to search for novel ways to manipulate DC development and activity, and to apply the findings to vaccine development and treatment of infectious disease and cancer.

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