Date of Award

Fall 12-22-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Yasmine Belkaid, Ph.D.

Second Advisor

Andrew Caton, Ph.D

Third Advisor

Christopher Hunter, Ph.D.; David Artis, Ph.D; Yongwon Choi, Ph.D.

Abstract

The gastrointestinal tract is replete with commensal microbes and dietary nutrients that provide homeostatic signals. Antigen presenting dendritic cells (DC) residing in the underlying lamina propria (Lp) respond to these signals; however, how they contribute to intestinal T cell homeostasis is unclear. In Chapter 2, LpDC are revealed to uniquely induce naïve T cell differentiation into the Foxp3+ regulatory T cell (Treg) subset. Further, the molecular mechanisms controlling this capacity both in vitro and in vivo are shown to hinge on the vitamin A metabolite, retinoic acid (RA), which LpDC are equipped to synthesize, and the cytokine, TGF-beta. T cell expression of retinoic acid receptor alpha (RARalpha) is shown to be critical for RA to induce enhanced Foxp3+ Treg induction. Chapter 3 extends upon these findings and addresses the influence of the commensal microbiota in the regulation of this pathway. A Toll like receptor (TLR) 9 ligand, commensal derived DNA, is identified as a potent adjuvant in the gut mucosa, which shapes T cell homeostasis in the GI tract. Accordingly Tlr9–⁄– mice display an intestinal site-specific increase in Foxp3+Treg concomitant with a decrease in TH cells. Dysregulation in Foxp3+ Treg/TH homeostasis results in mucosal-specific impaired immune responses in Tlr9–⁄– animals, which can be reversed upon partial depletion of Foxp3+ Treg. Chapter 4 builds upon findings from Chapter 2. The role of vitamin A metabolism in the regulation of mucosal immunity is examined. Vitamin A insufficient (VAI) mice, which lack vitamin A and metabolic derivatives, mount impaired mucosal TH-1 and TH-17 responses. These defects are reversed upon administration of RA. Moreover, Rara–⁄– mice recapitulate the homeostatic and immune defects observed in VAI mice. Strikingly, loss of basal RA/RARalpha signaling hinders early T cell activation events. Cumulatively, the data argue that steady-state cues from microbiota and nutrients shape the inflammatory tone of the Lp to prime mucosal TH responses. These data also identify a fundamental role for vitamin A metabolism in T cell activation and suggest this pathway may have evolved with the development of adaptive CD4+ T cell responses to coordinate host protection.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS