Investigating Enteric Glial Cell regulation of T-cell directed immune responses during infection and autoimmunity

The intestine is a highly complex organ responsible for digesting and absorbing nutrients while also serving as a frontline defense against ingested pathogens and toxins. This vital function relies on a diverse array of specialized cell types working in coordination to maintain gut homeostasis. Paramount to this regulation is the enteric nervous system, a vast network of specialized neurons and glial cells that orchestrate essential physiological processes. Among these, enteric glial cells (EGCs) have emerged as key modulators of intestinal homeostasis, particularly for their critical roles in regulating immune responses. A delicate balance in adaptive immunity is required to combat enteric infections while preventing excessive inflammatory responses that can drive autoimmunity. T cells play a pivotal role in this balance, coordinating immune responses against pathogens while also contributing to autoimmune disorders such as inflammatory bowel diseases (IBD). This underscores the need for further research into novel regulators of T cell responses in the gut. This dissertation reviews the roles of enteric glial cells in intestinal homeostasis and disease, exploring their novel functions in adaptive immune regulation. Specifically, we investigated whether EGCs contribute to T cell activation via antigen presentation. Reanalysis of single-cell RNA sequencing datasets from IBD patients revealed an upregulation of antigen presentation machinery in EGCs during disease. Using functional antigen presentation assays with primary EGC cultures, we demonstrated their capability for MHC I-mediated antigen presentation, including antigen cross-presentation, while MHC II-mediated presentation was not observed. Additionally, employing a model of acute Toxoplasma gondii infection, we confirmed that EGCs upregulate MHC I expression during disease, whereas MHC II expression is limited. Beyond enteric infections, we explored the potential role of T cell responses against EGC-derived antigens in multiple sclerosis (MS). Given that EGCs express myelin-associated antigens and that MS patients frequently experience gastrointestinal symptoms, we investigated their relevance in the experimental autoimmune encephalomyelitis (EAE) model. While we found a limited role for intestinal T cell responses in EAE, our findings suggest the potential for autoimmune targeting of ENS-derived antigens. Furthermore, we propose a novel model for selective EGC ablation to study their role in demyelinating diseases. In summary, this dissertation highlights emerging roles for enteric glial cells in regulating adaptive immune responses within the gut. Our work provides functional evidence of EGC antigen presentation and its implications in infection and autoimmunity, raising new questions about the broader impact of enteric glial cells in intestinal immune regulation.