Pathogenic Potential ofCD4 T Cells in Autoimmune Diseases

Abstract

The molecular mechanisms governing T helper (Th) cell differentiation and function have revealed a complex network of transcriptional and protein regulators. Cytokines not only initiate the differentiation of CD4 T helper into subsets, but also influence the identity, plasticity and effector function of a T cell. Th17 cells, named for producing interleukin 17 (IL-17) as their signature cytokine, secrete a cohort of other cytokines including IL-22, IL-21, IL-10, IL-9, IFNγ, and GM-CSF. In recent years, Th17 cells have emerged as a key player in host defense against both extracellular pathogens and fungal infections. Th17 cells have also been implicated as one of the main drivers in the pathogenesis of autoimmune diseases such as multiple sclerosis, which are likely mediated in part by the cytokines that Th17 cells produce.

Here in this thesis, we explore the pathogenic regulation of CD4 T cells in the context of the autoimmune diseases, multiple sclerosis and inflammatory bowel disease. We attempt to understand the mechanisms by which Th17 cells promote pathogenic inflammation by utilizing high throughput whole genome mRNA sequencing as well as next generation single cell RNA sequencing to uncover novel regulators that drive effector function. Advances in high throughput genomic sequencing allowed us to uncover an unexpected heterogeneity and diversity in Th17 cell populations. The four studies outlined in this thesis reconcile many confounding questions in the areas of autoimmune pathogenicity and reveal key regulators that define the various functional states of Th17 cells.