Dendritic cells (DCs) are specialized sentinel cells whose functional impairment is implicated in chronic inflammation, autoimmunity and carcinogenesis. Identification of factors regulating their functional development will further elucidate the mechanisms by which DCs mediate immunity and contribute to disease. DCs undergo a rapid functional maturation and activation upon exposure to pathogens. Functionally mature DCs are characterized by immune activities such as cytokine secretion, migration to secondary lymphoid tissues, and lymphocyte priming. Although several factors regulating early DC development have been identified, little is known about the regulation of their terminal differentiation and pathogen-induced functional responses. Because DCs are normally quiescent but ?primed? for rapid responses, these states are likely controlled by epigenetic mechanisms which influence transcriptional activity at many genetic loci. Our preliminary work has identified a histone-modifying enzyme that may regulate the terminal differentiation of DCs. I propose to investigate its requirement in DC differentiation and function using both genetic deletion (a DC-specific conditional knockout) and pharmacologic inhibition. Specifically, I will characterize the number and phenotype of resulting DCs in vivo and in culture (Aim 1), their functional properties (Aim 2) and their chromatin landscape (Aim 3). Collectively, the studies will provide novel mechanistic insights into the epigenetic control of DC differentiation and function, elucidate the involvement of histone-modifying regulators in immune pathology, and provide rationale for their therapeutic targeting.
Identifying epigenetic regulators of dendritic cell development is critical, as their functional impairment is implicated in chronic inflammation, autoimmunity and cancer. Our study will elucidate the role of a candidate epigenetic regulator in dendritic cell development, and provide rationale for its therapeutic targeting in immune pathology.
|Grajkowska, Lucja T; Ceribelli, Michele; Lau, Colleen M et al. (2017) Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification. Immunity 46:65-77|