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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZDK1-GRB-9)
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University of California San Diego
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