All ETDs from UAB

Advisory Committee Chair

Charles O Elson

Advisory Committee Members

Yingzi Cong

John F Kearney

Robinna G Lorenz

Suzanne M Michalek

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Host immune responses to the commensal microbiota are tightly controlled. Multiple levels of regulation reinforce intestinal homeostasis, including regulation by mucosal dendritic cells (DCs), regulatory T (Treg) cells, and the microbiota itself. However, the mechanisms involved are still largely unknown. Our current studies indicate that mucosal DCs originate and develop in the bone marrow, the latter of which is driven by retinoic acid (RA). Bone marrow cells express the RA-synthesizing enzyme ALDH, and provide RA to DC precursors in the bone marrow niche. RA induces DCs to express gut-homing CCR9 and ALDH1a2, and endows them with the ability to promote Treg cells. TLR/MyD88 signaling enhances RA-educated DC ALDH1a2 expression, and is required for optimal TGF-ß production and thus induction of Treg cells. However, Treg cells are not stable. Under certain conditions, Treg cells convert into Th1 and Th17 cells, as well as Foxp3+IFN-γ+ T cells in the intestine. The converted Foxp3+IFN-γ+ T cells retain regulatory functions to suppress effector T cell-induced colitis, and represent a transition state of Treg cell conversion to Th1 cells. The commensal microbiota actively shapes intestinal immune responses to itself. We show that beyond the T cell receptor-dependent antigenicity, microbiota activates innate DCs to produce IL-6 via TLR/MyD88 signaling, which in turn stimulates T cell proliferation. Microbiota TLR ligand-driven T cell spontaneous proliferation and antigen-specific T cell activation are both required for the induction of experimental colitis. Microbiota TLR ligands serve as adjuvants through interactions with TLRs on host immune cells. We show that TLR5, the receptor for bacterial flagellin, is highly expressed on mucosal DCs, whereas TLR4 is not. TLR ligands and host factors such as RA and stromal cells differentially regulate DC TLR5 expression. TLR5 engagement limits Treg cell generation, and promotes effector T cell responses. Thus, TLR5 signaling in the gut is crucial in maintaining homeostasis via modulation of effector/Treg cell balance. Taken together, our studies reveal a multifaceted interaction between the host immune system and microbiota. Appreciation of these interactions during health and disease may direct therapeutic approaches to a broad range of autoimmune and inflammatory disorders in humans.

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