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

Peripheral Treg cells (pTreg cells) maintain immune homeostasis at mucosal interfaces, where they can develop upon activation of naïve CD4+ T cells by bacteria antigen. However, the cellular and molecular requirements that govern their differentiation in inflamed and homeostatic contexts require further elucidation. To circumvent uncertainties in existing methods of distinguishing pTreg cells from thymic Treg cells (tTreg cells), we analyzed monoclonal cell populations of CT2 and CT6 transgenic (Tg) cells that develop into pTreg cells in response to different species of endogenously presented Helicobacter antigen. In our comprehensive assessment of multiple intestinal inflammatory models, including infections and physical injury, we find that pTreg development against Helicobacter antigen is largely preserved. In one model, DSS coupled with a high-fat diet (HFD), we observed a TCR-specific defect in Treg cell development with CT6, but not CT2 Tg cells, adopting effector fates. The concurrent development of effector and pTreg cells during inflammation implicate that the cellular and molecular signals that govern pTreg cells and effector T cell development are highly sequestered, protecting the host from the aberrant generation of effector T cells against tolerogenic antigens.

Transcriptional regulators regulate pTreg celll development by promoting FoxP3, antagonizing alternative effector fates, and stabilizing FoxP3 expression. Here, we capture transcriptional snapshots of activated monoclonal CT6 Tg cells pre and post FoxP3 expression to identify relevant transcriptional regulators during different stages of development. Early developing pTreg cells exhibit a burst of transcriptional activity that is not maintained in later stages. Furthermore, early developing pTreg cells transiently express Eomesodermin (Eomes) which restrains FoxP3 expression in activated, undivided cells and cells that have undergone one division. Eomes expression correlated with the expression of Nr4a family of transcription factors, which enhance FoxP3 expression. Thus, early developing pTreg cells concurrently express transcriptional regulators that promote or repress Treg cell development early in development.

Language

English (en)

Chair and Committee

Chyi-Song Hsieh

Committee Members

Paul M. Allen, Kenneth M. Murphy, Wayne M. Yokoyama, Gwendalyn J. Randolph,

Comments

Permanent URL: https://doi.org/10.7936/K7JH3KK5

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