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Date of Award

Spring 5-15-2018

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 professional antigen presenting cells conventionally thought to mediate cellular adaptive immune responses. DC diversification into functional subsets provides for modules of pathogen sensing and cytokine production that direct pathogen-appropriate ILC and T cell responses. Four different lineages can be classified as DCs: classical DCs (cDCs), plasmacytoid DCs (pDCs), monocyte derived DCs (Mo-DCs) and Langerhans cells. cDCs can then be divided into two subsets the IRF8 expressing DC1 and the IRF4 expressing DC2. While many of the transcriptional requirements for the development and function of DC1s are now known, those regulating the actions of Mo-DCs and DC2s remain unclear. We found that Ly-6ChiTremL4– monocytes can differentiate into Zbtb46+ Mo-DCs in response to GM-CSF and IL-4, but that Ly-6ChiTremL4+ monocytes were committed to differentiate into Ly-6CloTremL4+ monocytes. Differentiation of Zbtb46+ Mo-DCs capable of efficient cross-priming required both GM-CSF and IL-4, and was accompanied by induction of Batf3 and Irf4. However, monocytes require IRF4, but not Batf3, to differentiate into Zbtb46+ Mo-DCs capable of cross-priming CD8+ T cells. Instead, Irf4–/– monocytes differentiate into macrophages in response to GM-CSF and IL-4. Manipulation of Mo-DCs in vitro could enhance their potential as DC vaccines in cancer therapeutics.

A single master regulator of DC2 development has yet to be identified. The transcription factor RelB has been thought to be required for DC2 development. We found that DC development was independent of a cell-intrinsic action of RelB in most tissues, and that only the terminal maturation of Notch2-dependent splenic cDC2 cells was partially reduced in the absence of cell-intrinsic RelB expression. Moreover, the profound myeloid expansion seen in Relb–/– mice was due to an unrecognized action of RelB in non-hematopoietic cells, indicating that RelB is a critical component of the niche regulating the normal myeloid compartment. Notch2 signaling regulates the terminal maturation of cDC2s in the spleen and gut. In the gut, Notch2-dependent DC2s are the obligate source of IL-23 for survival against C. Rodentium infection. We extended our analysis of the in vivo function of Notch2-dependent cDCs by examining TFH differentiation and GC responses in response to several forms of immunization. We found that the Notch2-dependent ESAM+ cDC2 subset is required in two models of inducible TFH differentiation and GC reaction. We substantially extended our previous analysis of the genetic response induced in cDC2 by Notch2-signaling both at homeostasis and after immunization inducing TFH differentiation. Notably, we found that the inherent capacity for CD4 T cell priming in response to various amounts of soluble antigen by cDC2s was repressed by Notch2 signaling. Our studies have extended the understanding of the transcriptional pathways regulating the development and function of this lineage. Targeting of these pathways in this cDC subset may be useful for enhancing immunity and vaccine responses.

Language

English (en)

Chair and Committee

Kenneth M. Murphy

Committee Members

Brian T. Edelson, Takeshi Egawa, Deborah J. Veis, Emil R. Unanue,

Comments

Permanent URL: https://doi.org/10.7936/K7WS8SQ6

Available for download on Sunday, May 15, 2118

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