This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.

ORCID

https://orcid.org/0000-0002-6650-5955

Date of Award

Summer 8-15-2015

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

Gut commensal bacteria shape the colonic regulatory T (Treg) cell population required for intestinal homeostasis. However, little is known about this process. Here, we use the transfer of naïve transgenic T cells expressing colonic Treg TCRs to study gut Treg cell development in normal hosts. T cells were initially activated primarily in the distal mesenteric lymph node; Treg cell differentiation started within 2 days and with Foxp3+ cells in the most divided population, demonstrating that peripheral Treg cell generation can be the dominant outcome from naïve T cell activation. Various cell intrinsic and cell extrinsic elements are needed for this conversion. TGFβ is canonically said to be required for pTreg development, but TGFβ-receptor blockade in transferred cells only reduced, but did not abrogate Foxp3 expression. Additionally, cell-intrinsic signaling through the CNS1 region in the Foxp3 locus was required for early, but not late, Foxp3 induction. Though environmental influences also affect pTreg development, and decreased conversion was seen in C. rodentium infection and DSS induced inflammation, a regulatory fate was still the dominant differentiation outcome. Additionally, pTreg conversion is partially reliant on Notch2-dependent DCs during homeostasis.

Language

English (en)

Chair and Committee

Chyi Hsieh

Committee Members

Paul Allen, Marco Colonna, Kenneth Murphy, Thaddeus Stappenbeck

Comments

Permanent URL: https://doi.org/10.7936/K70R9MN6

Available for download on Thursday, August 15, 2115

Share

COinS