Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Yasmine Belkaid

Second Advisor

Phillip Scott

Abstract

Tissue-infiltrating Ly6Chi monocytes play important protective roles during infection, including inflammatory cytokine secretion and pathogen killing. Here we show that during acute gastrointestinal infection with the protozoan parasite Toxoplasma gondii, recruited monocytes not only contributed to parasite control, but also regulated pathologic immune responses to commensal microbes via secretion of the lipid mediator prostaglandin E2 (PGE2). Priming of monocytes for regulatory function preceded systemic inflammation and was initiated prior to bone marrow egress. Natural killer (NK) cell-derived IFN-γ promoted a regulatory program in monocyte progenitors during development. Early bone marrow NK cell activation was controlled by systemic IL-12 produced by Batf3-dependent dendritic cells (DC) in the mucosal-associated lymphoid tissue (MALT). This work challenges the paradigm that monocyte function is dominantly imposed by local signals following tissue recruitment, and instead proposes a sequential model of differentiation in which monocytes are pre-emptively educated during development in the bone marrow to promote their tissue-specific function.

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