T helper (Th) cells in lymphoid tissues, depending on their location, develop into various Th subsets to regulate inflammation and defense. In the intestinal mucosa, their dominant phenotype is that of regulatory T (Treg) cells. Mucosal adjuvant, by overriding the tolerizing impact of mucosal Treg cells, are unique tools for dissecting immune regulation and inflammation. Our preliminary data indicate that cholera toxin (CT) and related compounds induce Thi7 cell differentiation via a cAMP-dependent and IL-6/TGF(3-independent pathway. To elucidate the mechanism by which adenylyl cyclase toxins and other luminal microbial products (TLR ligands) stimulate and modulate the mucosal microenvironment to promote effector Thi7 responses, we propose in Aim 1 to define how oral CT administration enhances Th17-promoting dendritic cells (DC) and suppresses Treg-promoting DC. We will explore the role of cAMP and retinoic acid in these processes, and characterize the subsequent Th cell response provoked by different MLN DC subsets.
In Aim 2, we will characterize the phenotype, stability and lineage differentiation markers of CD4 T cells from in vitro- and in vivo-differentiated CT-induced Thi7 subsets, and evaluate the inflammatory/regulatory impact of orally delivered CT on the outcome of Thi7 cell-mediated colitis.
Aim 3 will explore the role of CGRPP produced by CT-activated DC in a mucosal Thi7 response.
Aim 4 will investigate the potential contributing role of TLR stimulation to CT-induced Thi7 differentiation. Dissecting the impact of CT and other cAMP-inducing compounds on mucosal DC maturation will significantly broaden our knowledge on the generation of mucosal Th responses. By dissecting the lineage stability of CT-induced mucosal Thi7 cells, their effector function, lineage commitment, trafficking and their interactions with other Th cells, we will increase our understanding of the regulation of inflammation and immunity at mucosal sites. The data generated in these studies may help to design new therapeutic approaches for mucosal inflammatory diseases and novel mucosal adjuvant.

Public Health Relevance

Mucosal adjuvant are critical for success of oral vaccination strategies, since antigen exposure alone does not elicit protective immunity. The studies are designed to increase the understanding of the mechanisms by which such adjuvant promote protective immunity, and will also generate new insights into the natural mechanisms by which the gut maintains normal immune homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK035108-28
Application #
8517650
Study Section
Special Emphasis Panel (ZDK1-GRB-9)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
28
Fiscal Year
2013
Total Cost
$210,464
Indirect Cost
$70,530
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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