All ETDs from UAB

Advisory Committee Chair

Robert S Welner

Advisory Committee Members

David Schneider

Allan Zajac

Chander Raman

Chris Klug

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In the bone marrow, Regulatory T cells (Tregs) constitute nearly 30% of CD4+ T cells, a significantly higher ratio than other tissues. Although a few of the mechanisms by which Tregs regulate normal hematopoiesis have been elucidated, our understanding of this process during leukemogenesis is ex-tremely limited. In this work, we define how Tregs maintain and support the bone marrow microenvironment. We propose that the role of Tregs extends be-yond their canonical immuno-suppressive function and that these cells are re-quired to maintain healthy hematopoiesis. We have defined tissue-specific roles for Tregs in the bone marrow including the maintenance of hematopoietic stem cells (HSCs) as well as crosstalk with mesenchymal stromal cells. We observed that depletion of Tregs has widespread effects across several bone marrow populations. Loss of Tregs induces proliferation and cycling of HSCs, and re-sults in accumulation of myeloid cells, all hallmark traits of neoplasia. Moreover, the supportive capacity of stromal niche populations is negatively altered by Treg depletion suggesting a remodeling of the marrow microenvironment. Spe-cifically, we underscore the importance of Treg IL-10 in maintaining stromal cell function and supporting hematopoiesis. We expand on these findings to show how that Tregs are altered in a leukemic setting and utilize immunotherapeutic agents to restore Treg function and mitigate leukemic transformation. These projects further examine how loss of Treg function and IL-10 regulatory mechanisms promote disease progression in the context of chronic myeloid leukemia. The findings presented here provide a foundation to devise more comprehensive immune therapies in myeloid ma-lignancies. Defining how and why Treg dysregulation occurs, as well as deter-mining specific mechanisms that are lost during leukemic transformation are the focus of these studies with the goal of improving our understanding of the im-mune landscape in hematological disease. The conclusions from this work pro-vide a direction for manipulating the trajectory of the immune response in mye-loid neoplasms.

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