While studying the mucosal adjuvant, cholera toxin, we recently identified It Induces Th17 cell differentiation via cAMP signaling. Canonical (I.e., induced by IL-6/TGF?) and non-canonical (i.e., induced by cAMP) Th17 subsets display different cytokine homing receptors and are regulated by different combinations of transcription factors. We hypothesize that these two Th17 subsets perform different physiological tasks especially at mucosal sites. To characterize the immunoprotective vs. immunopathogenic profiles of these Th17 subsets in the G-l mucosa, we proposed 4 specific aims (SA). In SA-1 we will characterize and compare the phenotype of the in vitro generated Th17 subsets after their adoptive transfer to recipient mice. Similarly, we will assess the inflammatory vs. regulatory function of each Th17 subset in a model of colitis. To explore the physiological role of cAMP signaling in Th17 differentiation in vivo, we generated ko mice that carry a specific deletion of the stimulatory Ga protein (Gsa) in CD4 T cells (GsaCD4 ko mice). Thus, in SA-2 we will evaluate the cytokine profile of GsaCD4 ko CD4 T cells, their homing properties to lymphoid organs and G-l mucosa, and their colitogenic profile in models of intestinal inflammation. In SA-3 we will evaluate whether GsaCD4 ko CD4 T cells mediate host protection against microbial pathogens, i.e., C. rodentium and H. pylori. We will examine the function of non-canonical Th17 cells in host defense, mucosal protection and mucosal inflammation. An important translational application of these studies is the design of cAMP-based pharmacological interventions that target the regulation of CD4 T cell functions in mucosal sites. Thus, in SA- 4 we will determine whether the administration of cAMP-elevating drugs regulate mucosal defense in the animal models described above. The results from our proposed research can facilitate the future design and development of vaccines and immunotherapies aimed at the protection of different mucosal surfaces from infections and immune-mediated pathology, which are the ultimate objectives of this RFA.
In this application we will investigate two subsets of lymphocytes in models of intestinal inflammation and infection. Using appropriate mice that we generated, we will determine which of this subset is protective and which is inflammatory in the gut. Using appropriate drugs, we will attempt to modulate the inflammatory cell to function in a protective mode.
|Bertin, Samuel; Aoki-Nonaka, Yukari; Lee, Jihyung et al. (2016) The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1. Gut :|
|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|
|Bertin, Samuel; Raz, Eyal (2016) Transient Receptor Potential (TRP) channels in T cells. Semin Immunopathol 38:309-19|
|Lee, Jihyung; Kim, Tae Hoon; Murray, Fiona et al. (2015) Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma. Proc Natl Acad Sci U S A 112:1529-34|
|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|
|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|
|GonzÃ¡lez-Navajas, JosÃ© M; Corr, Mary P; Raz, Eyal (2014) The immediate protective response to microbial challenge. Eur J Immunol 44:2536-49|
|Bertin, Samuel; Aoki-Nonaka, Yukari; de Jong, Petrus Rudolf et al. (2014) The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4âº T cells. Nat Immunol 15:1055-63|
|Lee, Shee Eun; Li, Xiangli; Kim, Joanna C K et al. (2012) Type I interferons maintain Foxp3 expression and T-regulatory cell functions under inflammatory conditions in mice. Gastroenterology 143:145-54|
Showing the most recent 10 out of 14 publications