Dendritic cell intrinsic UPR is critical for pathogen specific Th17 responses

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

Investigators

Abstract

Project Summary Following ac+va+on, CD4 T cells differen+ate into one of three main effector linages. The Th1, Th2 and Th17 lineage cells are generated in response to specific class of pathogens and are necessary to combat those infec+ons. While we have comprehensive understanding of the specific cytokine cues as well as master transcrip+on factors that are cri+cal for differen+a+on of each of these dis+nct T cell effector lineages, the innate sensing mechanisms that dictate specific differen+a+on of each of the T effector lineages are not clear. The pathogens that drive Th2 responses are fairly dis+nct but the Th1 and Th17 inducing pathogens share many structural similari+es. Classical paFern recogni+on receptor ac+va+on by microbial ligands leads to genera+on of inflammatory cytokine cues in the form of TNF, IL-6, IL-12, IL-1b, etc but we do not understand how CD4 T cells integrate specific cues to generate a Th1 vs Th17 response. We posit here that host sensing mechanisms that extend beyond the classical paFern recogni+on receptors might be involved in genera+ng unique cytokine cues that specifically dictate genera+on of Th1 vs Th17 lineage cells. Our previous work has demonstrated that following sensing of pathogens, conven+onal DCs can induce priming of naïve pathogen specific CD4 T cells in vitro and the quality of the T cell response is dictated by the nature of the priming pathogen. Specifically, s+mula+on of conven+onal DCs with the gut pathogen C. roden)um drives Th17 differen+a+on as opposed to L. monocytogenes, sugges+ng a DC-dependent mechanism for Th17 differen+a+on. Transcrip+onal profiling of DCs upon exposure to Th17 inducing (C. roden)um) versus non-inducing pathogens (L. monocytogenes and S. aureus) and discovered that C. roden+um induced ac+va+on of the PERK pathway of unfolded protein response (DC- UPR) that was integral to its ability to induce Th17 responses. C. roden+um’s ability to induce DC-UPR was shared by its counterparts, the human enteric pathogens, EHEC and EPEC sugges+ng that this property was evolu+onarily conserved in both the microbes and the hosts. More importantly, several autoimmune diseases caused by Th17 cells are associated with the Unfolded protein response sugges+ng an integral link between ER stress and outcome of T cell responses. In this applica+on we propose to inves+gate the importance of this UPR induc+on from the perspec+ve of the microbe as well as the host and dissect the molecular mechanisms of induc+on of the UPR and its impact on Th17 priming and differen+a+on. In aim 1, we will inves+gate the role of DC-UPR in driving tailored immune responses against Th17 inducing pathogens. In aim, 2 we will iden+fy and characterize the nature of the C. roden+um ligand that ac+vates the PERK pathway of UPR in DCs. In aim 3, we will inves+gate the conserved nature of the UPR pathway in human enteric pathogens and human myeloid cells. Successful comple+on of these aims will add to our fundamental understanding of genera+on of Th17 responses and will provide us with tools to either increase or mi+gate development of Th17 response to enhance protec+on against pathogens or protect against auto-immune inflamma+on.