The immune system is essential for maintaining a delicate balance between eliminating pathogens and maintaining tolerance to self-tissues to avoid autoimmunity. An enormous and complex community of gut microbiota provides essential health benefits to the host, particularly by regulating immune homeostasis. Many of the metabolites derived from commensals can impact host health by directly regulating the immune system. Many autoimmune diseases arise from an imbalance between pathogenic effector T cells and regulatory T (Treg) cells. Recent interest has emerged in understanding how cross-talk between gut microbiota and the host immune system promotes autoimmune development by controlling the differentiation and plasticity of T helper and Treg cells. At the molecular level, our recent study, along with others, demonstrates that asymptomatic colonization by commensal bacteria in the gut is capable of triggering autoimmune disease by molecular mimicking self-antigen and skewing the expression of dual T-cell receptors on T cells. Dysbiosis, an imbalance of the gut microbiota, is involved in autoimmune development in both mice and humans. Although it is well known that dysbiosis can impact diseases occurring within the gut, growing literature suggests that dysbiosis also causes the development of gut-distal/non-gut autoimmunity. In this review, we discuss recent advances in understanding the potential molecular mechanisms whereby gut microbiota induces autoimmunity, and the evidence that the gut microbiota triggers gut-distal autoimmune diseases.

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Regulatory T cells (Tregs) use a distinct TCR repertoire and are more self-reactive compared with conventional T cells. However, the extent to which TCR affinity regulates the function of self-reactive Tregs is largely unknown. In this study, we used a two-TCR model to assess the role of TCR affinity in Treg function during autoimmunity. We observed that high- and low-affinity Tregs were recruited to the pancreas and contributed to protection from autoimmune diabetes. Interestingly, high-affinity cells preferentially upregulated the TCR-dependent Treg functional mediators IL-10, TIGIT, GITR, and CTLA4, whereas low-affinity cells displayed increased transcripts for and, suggesting distinct functional profiles. The results of this study suggest mechanistically distinct and potentially nonredundant roles for high- and low-affinity Tregs in controlling autoimmunity.

Type 1 Diabetes (T1D) is a T cell-mediated autoimmune disease that is characterized by antigen specific targeting and destruction of insulin producing β cells. While multiple studies have characterized the pathogenic potential of β-cell specific T cells, we have limited mechanistic insight into self-reactive autoimmune T cell development and their escape from negative selection in the thymus. Here we demonstrate that ectopic expression of insulin B:9-23 (InsB9-23) by thymic antigen presenting cells is insufficient to induce deletion of high or low affinity InsB9-23 reactive CD4+ T cells; however, we observe an increase in the proportion and number of thymic and peripheral Foxp3+ regulatory cells T cells. In contrast, the MHC stable insulin mimetope (InsB9-23 R22E) efficiently deletes insulin specific T cells and prevents escape of high affinity thymocytes. Collectively, these results suggest that antigen dose and peptide:MHC complex stability can lead to multiple fates of insulin reactive CD4+ T cell development and autoimmune disease outcome.