instmctions): The simultaneous constraint of highly efficient protective immunity together with the prerequisite for tolerance towards innocuous antigens Imposes a significant challenge for the intesfinal mucosal immune system. Several mechanisms operating in different types of DCs and/or T cells have been identified that control immune tolerance and protective immunity. TGF-|3 in particular is a crucial regulator capable of inducing FoxpS+Tregs, but paradoxically, in the presence of pro-inflammatory cytokines, promoting the conversion to Thi7 effector cells. This contrasting deviation puts TGF-(3 as a principal controller of pro- and anti-inflammatory immune responses. Recently we demonstrated that retinoic acid and other retinoids function as key regulators of the TGF-P-dependent immune deviation, capable of inhibiting the induction of proinflammatory Thi7 cells but promoting the TGF-P-dependent differentiation of anti-inflammatory FoxpS+lTregs. We further showed that in the absence of innate danger signals, retinoids can be absorbed and released by the DCs to the T cells they prime. The released retinoids then directly target differential gene expression within the T cell to promote anti-inflammatory and tolerant immunity. In the presence of danger signals sensed by the DCs, retinoids no longer suppress pro-inflammatory differentiation of primed T cells, suggesting that under innate stimulation conditions, retinoid-mediated suppressive effects on T cells are abolished and/or that retinoid signaling in the presence of innate stimuli can turn towards the DCs and promote their antigen presenting function and protective immune responses. The study proposed here, aims at elucidating retinoid-mediated mechanisms that operate in T cells or DCs and that control the balance between tolerance and protective immunity. The indicated collaborative approaches with Units 1,2 and 3 of this PPG, will allow us to extend this study and evaluate the potential cross talk between the retinoid pathways and other cellular mechanisms involved in immune regulation, as well as the role of retinoid-mediated control in directing immune responses towards specific pathogens, using various infecfious animal models.

Public Health Relevance

The knowledge gained from this study will expand our understanding of regulation of pro- and anti? inflammatory immune responses, in particular involving mechanisms employed by the mucosal immune system to control local and systemic immunity. The study has also great potential for the identiflcation of new drug targets that may improve exisfing therapies or may lead to the development of novel medical intervention opportunities to prevent and/or treat intestinal inflammatory diseases.

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 #
8517656
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
$251,737
Indirect Cost
$111,930
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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 :
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, 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
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
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
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
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

Showing the most recent 10 out of 253 publications