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, fheir dominant phenotype is that of regulatory T (Treg) cells. Mucosal adjuvants, by overriding the tolerizing impact of mucosal Treg cells, are unique tools for dissecting immune regulation and inflammafion. 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 administrafion 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 infiammatory/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 significantiy 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 adjuvants.

Public Health Relevance

Mucosal adjuvants 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 adjuvants promote protective immunity, and will also generate new insights into the natural mechanisms by which the gut maintains normal immune homeostasis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-9)
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University of California San Diego
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Bertin, Samuel; Aoki-Nonaka, Yukari; Lee, Jihyung et al. (2017) The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1. Gut 66:1584-1596
Lakhdari, Omar; McAllister, Christopher S; Wang, Michael et al. (2016) TLR3 signaling is downregulated by a MAVS isoform in epithelial cells. Cell Immunol 310:205-210
de Jong, Petrus R; Taniguchi, Koji; Harris, Alexandra R et al. (2016) ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation. Nat Commun 7:11551
Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina et al. (2016) Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules. J Leukoc Biol 99:475-82
de Jong, P R; Takahashi, N; Peiris, M et al. (2015) TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP. Mucosal Immunol 8:491-504
Vicente-Suarez, I; Larange, A; Reardon, C et al. (2015) Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal Immunol 8:141-51
Wang, Kepeng; Karin, Michael (2015) The IL-23 to IL-17 cascade inflammation-related cancers. Clin Exp Rheumatol 33:S87-90
Dann, Sara M; Manthey, Carolin F; Le, Christine et al. (2015) IL-17A promotes protective IgA responses and expression of other potential effectors against the lumen-dwelling enteric parasite Giardia. Exp Parasitol 156:68-78
Bertin, S; Lozano-Ruiz, B; Bachiller, V et al. (2015) Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice. Mucosal Immunol 8:505-15
de Jong, Petrus R; Takahashi, Naoki; Harris, Alexandra R et al. (2014) Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis. J Clin Invest 124:3793-806

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