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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

The dendritic cells (DCs) of the immune system function in innate and adaptive responses by directing activity of various effector cells rather than serving as effectors themselves. DCs and closely related myeloid lineages share expression of many surface receptors, presenting a challenge in distinguishing their unique in vivo functions. Recent work has taken advantage of unique transcriptional programs to identify and manipulate murine DCs in vivo. This work has assigned several non-redundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs (pDCs) and several subsets of classical DCs (cDCs) that promote different immune effector modules in response to pathogens. Batf3 is expressed in all classical cDCs, but is selectively required for development of the CD8α+ cDC lineage. However, the basis for Batf3 specificity and its precise role in CD8α+ cDCs is completely unknown. Here, we identify two novel clonogenic progenitors that separately give rise to CD8α+ cDCs or CD4+ cDCs. These pre-CD8 DC and pre-CD4 progenitors arise directly from the common DC progenitor (CDP), and gene expression profiling defines them as distinct from both CDPs and mature DCs. We find that Id2 and Batf3 are factors induced early in specification of pre-CD8, but not pre-CD4, DC progenitors. The pre-CD8 DC progenitor can develop in the absence of Batf3, but not in the absence of IRF8. We show that IRF8 expression in the pre-CD8 DC progenitor is controlled by Irf8 autoactivation at a Batf3-dependent Irf8 superenhancer containing an AICE that is active exclusively in CD8α+ cDCs. In the absence of Batf3, the CDP undergoes specification to the pre-CD8 DC progenitor, but fails to commit to the CD24+ lineage due to decay of Irf8 autoactivation, and instead diverts to the CD172a+ lineage.

Language

English (en)

Chair and Committee

Kenneth M. Murphy

Committee Members

Deepta Bhattacharya, Marco Colonna, Brian Edelson, Takeshi Egawa,

Comments

Permanent URL: https://doi.org/10.7936/K7ST7P9M

Available for download on Sunday, May 15, 2118

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