All ETDs from UAB

Advisory Committee Chair

Casey T Weaver

Advisory Committee Members

Etty N Benveniste

Stuart J Frank

Laurie E Harrington

Louis B Justement

Robinna G Lorenz

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Naïve CD4 T cells differentiate into a variety of phenotypically and functionally distinct subsets uniquely tailored to the specific inflammatory context. Despite the extraordinary heterogeneity of potential fate outcomes, two distinct but related functional bifurcations appear common to all inflammatory contexts. Following activation, CD4 T cells either home to the site of inflammation and influence peripheral events or remain in the secondary lymphoid tissue to modulate central processes. Similarly, activated cells either drive or suppress inflammation. These functional bifurcations are coincident and sufficiently independent to allow for the simultaneous generation of all four potential outcomes. Pro-inflammatory cells retained in the lymphoid tissue develop into T follicular helpers (Tfh), while traditional non-Tfh effector subsets migrate to the periphery. Each exists in mutual opposition to a specific anti-inflammatory counterpart. Induced regulatory T cells (iTreg cells) suppress peripheral inflammation, while T follicular regulatory cells (Tfr) are found in secondary lymphoid tissues. These populations develop in response to all major pathogen types and in the context of autoimmunity, and undergo similar qualitative changes relevant to the specific inflammatory context. Thus, the complexity of CD4 T cell differentiation can be collapsed into discrete binary outcomes along two functional dimensions. Application of this conceptual framework allows for the identification of factors and processes relevant to a broad array of inflammatory contexts and informs experimental design. Intentional isolation of a single functional axis simplifies experimental results into binary outcomes. Thus we have pursued two separate sets of studies, each designed to examine a different functional dimension. In the first set of experiments, we show that differential expression of IL-2 by recently activated naïve cells defines precursors fated for central versus peripheral function, with the Tfh compartment exclusively supplied by former IL-2 producers. The transcriptional bifurcations underlying these fate outcomes occur simultaneously, precede cell division, and are directly linked to TCR signal strength. In the second set of experiments, we address the development of pro-inflammatory and suppressive populations. We show that insulin-like growth factors (Igfs) reciprocally regulate the differentiation of iTreg and Th17 cell populations, biasing both the amplitude and quality of the pro-inflammatory response. Igfs suppress iTreg cell differentiation, augment Th17 cell development, and enhance expression of key effector genes in mature Th17 cells.

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