Th17 cells are an Interleukin-17-producing subset of CD4+ T effector cells that are centrally implicated in many human inflammatory and autoimmune diseases, from inflammatory bowel disease to multiple sclerosis. The retinoid orphan receptor gamma t (ROR?t), a nuclear hormone receptor, programs Th17 cell development and function. With the ultimate goal of modulating inflammatory T cells in disease settings, we undertook chemical and genetic screening to identify ROR?t target genes that drive human Th17 cell function. Intriguingly, our results implicated a group of genes in a novel pathway that would link lipid metabolism, ROR?t activity and Th17 cell functions. We will thus test the hypothesis that Th17 cell function is controlled in large part, by ROR?t target genes, via lipid droplets (LDs) (cellular organelles associated with lipid metabolism). We will take the following approaches: First, we will determine if LD- related genes ? specifically, HILPDA and BNIP3 ? are necessary, sufficient and specific regulators of human Th17 cell functions. Second, we will elucidate the molecular mechanisms by which LDs modulate Th17 cell differentiation. Third, using autoimmune disease models in mice, we will determine the physiological significance of LDs in inflammation and autoimmune pathologies. Our results may shed a light on novel lipid-regulatory mechanisms that control Th17 cell responses in inflammatory diseases.
The lipid-regulatory mechanisms underlying autoimmune diseases and the biogenesis of pathogenic IL-17 producing T helper cells (Th17) are poorly understood. I propose to combine genetic and chemical approaches, to reveal how Th17 cell activities are regulated in a lipid organelle-dependent manner. The results may reveal new strategies for the treatment of human autoimmune inflammation.
| Shin Yim, Yeong; Park, Ashley; Berrios, Janet et al. (2017) Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 549:482-487 |
| Kim, Sangdoo; Kim, Hyunju; Yim, Yeong Shin et al. (2017) Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549:528-532 |
