This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.

ORCID

http://orcid.org/0000-0001-9286-5789

Date of Award

Spring 5-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Dendritic cells (DCs) are innate immune cells of the myeloid lineage that are specialized at pathogen recognition, cytokine production, and antigen presentation. Their functions and developmental pathways are largely conserved between mice and humans and mice. The DC lineage is composed of two major subsets, known as plasmacytoid DCs (pDCs) and classical DCs (cDCs). Research conducted to date suggests that the function of pDCs, limited to viral antigen recognition and type I interferon production, can be compensated by other immune cell lineages. On the other hand, there is a consensus that diversified subsets cDCs in mice and humans are essential regulators of innate and adaptive immune responses with non-redundant functions in recognition of viral, bacterial, and parasitic infections; the production of specific cytokines to regulate pathogen clearance and adaptive lymphocyte polarization; the activation of antigen-specific CD4+ and CD8+ T cells during primary and secondary immune responses; the regulation of inflammatory responses required to generate antigen-specific immune responses to cancer; and the generation of tolerance to self, commensal, and dietary antigens to inhibit autoimmunity and allergies. The original research presented in this dissertation advances our understanding of the transcriptional mechanisms that regulate DC function and development. The function and development of cellular lineages are generally regulated by a limited but unique combination of transcription factors that establish the subset-specific transcriptional programs and, in turn, regulate distinct developmental pathways and cellular functions. To that end, we studied the roles of the following transcription factors in the regulation of the transcriptional identity, function, and development of DCs using genetic knockout and reporter mouse lines generated previously. First, we examined determined that the regulation of transcription by CIITA in cDCs is highly restricted to the major histocompatibility class II locus, thereby refuting previous claims that CIITA more broadly regulates a transcriptional program of antigen processing and presentation in DCs. Next, we followed up on a previous discovery in the lab that MYCL, which is specifically expressed by DCs, supports CD8+ T cell priming. Whole-transcriptome analysis of Mycl-deficienct mice revealed that MYCL supports the fitness of DCs by broadly supporting steady state levels of transcription of genes biosynthetic processes. Finally, we examined the role of IRF8 in the regulation of a transition from MYC dominance in multipotent progenitors to MYCL dominance in specified DC-restricted progenitors in the bone marrow, revealing a novel mechanism axis of gene regulation for the MYC family of genes during hematopoiesis, as well as putative mechanisms of direct activation and repression of Myc and Mycl transcription by IRF8. Together, this work advances our understanding of the in vivo transcriptional mechanisms that regulate DC development and function.

Language

English (en)

Chair and Committee

Kenneth M. Murphy

Committee Members

Takeshi Egawa, Robert Schreiber, Brian Edelson, David DeNardo,

Available for download on Thursday, March 16, 2023

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