Title

Investigating Human Neutrophil Development and Functionality in a Humanized Mouse Model

Date of Award

Fall 10-1-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Flavell, Richard

Abstract

Mice with a functional human immune system serve as an invaluable tool to study the development and function of human immune system in vivo. A major technological limitation of all current humanized mouse models is the lack of mature and functional human neutrophils in circulation and tissues. To overcome this, we generated a humanized mouse model named MISTRGGR, in which the mouse granulocyte colony stimulating factor (G-CSF) was replaced with human G-CSF and the mouse G-CSF receptor gene was deleted (G-CSFR) in existing MISTRG mice. By targeting the GCSF cytokine-receptor axis, we dramatically improved the reconstitution of mature circulating and tissue-infiltrating human neutrophils in MISTRGGR mice. Moreover, these functional human neutrophils in MISTRGGR are recruited upon inflammatory and infectious challenges and help reduce bacterial burden. Neutrophils have long been regarded as simple effector killer cells in antimicrobial defense, yet more recently, there’s been growing appreciation on neutrophils’ functional diversity in immune surveillance and tissue homeostasis. As investigating human neutrophil biology remains challenging both in vitro and in animal models, MISTRGGR mice represent a unique mouse model that finally permits the study of human neutrophils in health and disease.

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