TLR2-dependent bystander activation of T cells results in exacerbation of Lyme arthritis

Abstract

Abstract Infection with the bacteria Borrelia burgdorferi results in a multidimensional disease including, fever, headache, arthritis, and a characteristic skin rash. When left untreated, bacteria can disseminate to multiple parts of the body including joints, heart, and nervous system. Approximately 10–20% of patients treated with antibiotic therapy for Lyme disease will continue to have persistent symptoms for months or years. T cells predominate the immune response in the synovial fluid of these patients; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4+ and CD8+ T cells leads to the secretion of arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with post-treatment Lyme disease (PTLD). T cell receptor (TCR) transgenic mice containing monoclonal specificity towards non-Borrelia epitopes confirmed that bystander T cell activation was responsible for disease development. RNA-sequencing of bystander activated T cells provided insight into the molecular characteristics of non-classical T cell activation. The microbial pattern recognition receptor Toll-like receptor 2 (TLR2) was upregulated on T cells following infection, implicating it as marker of bystander T cell activation. In fact, T cell intrinsic expression of TLR2 contributed to IFN-γ production and arthritis, providing a mechanism for microbial-induced bystander T cell activation during infection. These results reveal a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broader application to bystander T cell activation and immune pathogenesis.