Innate mechanisms of regulation of Th17 responses

点击翻译按钮获取中文摘要

Project Summary/Abstract Induction of inflammation by canonical microbial ligands by engaging classical patten recognition receptors (PRR) has many beneficial outcomes including elimination of the pathogen and activation of adaptive immunity that serves as protection against reinfection. However, unwarranted inflammation can also be induced by aberrant activation of PRRs by noxious agents (toxins, uric acid etc) or because of naturally occurring mutations in sensors or adapters of the innate immune system leading to auto-inflammatory diseases such as Cryopyrin Associated Inflammatory Syndromes, and Interferonopathies. Auto-immune diseases on the other hand are different than auto-inflammatory diseases as the culprits that trigger pathology are self-reactive T and B cells. Auto-immune inflammation can lead to debilitating outcomes because of damage to vital organs such as kidney, pancreas intestines as well as Skin and joints. Paradoxically, many of the clinical treatments for T cell auto-immune diseases are all directed towards inflammatory cytokines made by the innate immune system. Our previous work demonstrated that effector and effector memory CD4 T cells have the capacity to drive IL-1b production, completely independent of pattern recognition receptor activation. We discovered that Effector CD4 T cells provide both signal 1 (TNFa) and signal 2 (FasL) to instruct the myeloid cells to produce IL-1b in a Caspase-8 dependent manner. The current proposal is based on very strong preliminary data that demonstrates that effector CD4 T cells in fact have the capacity to mimic microbial ligands to drive a broad pro-inflammatory program in cells of the innate immune system. We find that effector memory CD4 T cells induce additional genes in Dendritic cells that sets up important questions related to “T cell instruction” of the innate immune system. Here we posit that while proximal activation of PRRs is necessary for naïve T cell activation, effector memory T cells have the ability to directly activate the innate immune system thus bypassing the need for PRR sensing. Although this might have evolved as a beneficial arm of the innate adaptive cross-talk, we propose to understand the detrimental outcomes of adaptive instruction of innate immunity in driving inflammation and tissue pathology. In order to gain mechanistic understanding of innate inflammation driven by effector CD4 T cells, we propose three aims where 1. We will examine and characterize the nature of innate inflammation driven by different effector memory T cell lineages and identify the molecular players involved in this process, 2. We will investigate the molecular mechanisms by which effector memory CD4 T cells drive innate inflammation with a particular focus on STING and DNA damage and 3. We will examine the impact of CD4 T cell effector/effector memory CD4 T cell driven innate inflammation on auto-immune disease and pathology. Successful completion of these aims will provide novel insights into T cell driven innate inflammation independent and will open up new targets to treat auto-immune diseases.