Daniel Fernando Zegarra-Ruiz

Autoimmune diseases are a major health problem affecting over 200 million people worldwide and represent one of the leading causes of death for women under 65 years old. Although these pathologies are increasing in prevalence and often lead to multi-organ dysfunction, current treatments for autoimmune diseases are mostly aimed at suppressing the immune system without treating the cause, which usually leads to serious side effects and long-term sequelae. Therefore, finding safer approaches is key to effectively controlling these chronic and debilitating disorders. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease leading to chronic inflammation in multiple organs due to adaptive immune responses to self-antigens. Although the etiology of autoimmunity remains unknown, multiple autoimmune diseases, including SLE, are linked with intestinal dysbiosis. Dysbiosis is characterized by alterations of the gut microbial communities, which can exhibit pathobiont overgrowth and/or loss of beneficial bacteria. We and others have shown that lupus development is linked with intestinal dysbiosis in patients and mouse models. I previously found an increase in pathobionts such as Lactobacillus reuteri and Enterococcus gallinarum in lupus mouse models and subsets of SLE patients. Strikingly, in mouse models, intestinal overgrowth of these pathobionts was followed by intestinal permeability and systemic translocation, which dysregulated immune pathways leading to increased systemic inflammation and worsened lupus pathogenesis. In SLE, we showed that microbiota-specific T cell responses occur; however, how microbiota-specific T cells arise and modulate lupus progression is not known. Therefore, in my postdoctoral training I focused on how generation and differentiation of microbiota-specific T cells are regulated during postnatal development. While we and others find peripheral expansion of microbiota-specific T cells in adult mice, surprisingly in young mice we found microbiota-specific T cells first expanded in the thymus, a site not previously known to allow for antigen-specific T cell expansion. Upon bacterial re-encounter these cells differentiated into microbiota-specific effector T cells and exacerbated intestinal inflammation in immunodeficient hosts. Our data suggests that intestinal colonization controls the development of thymic microbiota-specific T cells which can modulate inflammatory processes. Because of these findings, my research aims to determine how microbiota-specific T cells, environmental factors, and intestinal inflammation modulate lupus pathogenesis.