IL-10 Deficiency Reveals a Role for TLR2-Dependent Bystander Activation of T Cells in Lyme Arthritis

Abstract

T cells predominate the immune responses in the synovial fluid of patients with persistent Lyme arthritis; 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 arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with posttreatment Lyme disease. TCR transgenic mice containing monoclonal specificity toward non- epitopes confirmed that bystander T cell activation was responsible for disease development. The microbial pattern recognition receptor 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. The IL-10-deficient mouse reveals a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broad application to immune pathogenesis.

Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious,Borrelia burgdorferi‐induced Lyme arthritis

“…In mice, dysregulated Type I (IFNα/β) or Type II IFN (IFNγ) production is associated with severe LA (Lochhead et al, ; Sonderegger et al, ; Whiteside et al, ). Therefore, Interferome analysis (Rusinova et al, ) was performed to identify the percentage of IFN‐upregulated genes from those upregulated in LA synovial tissue compared with OA or other forms of chronic inflammatory arthritis (Figure a).…”

“…Arthritogenic C3H/HeN and C57BL/6 Il10 −/− mice have robust upregulation of IFN‐response pathways in infected joints early in infection that negatively correlate with expression of tissue repair genes (Crandall et al, ). This phenotype is dependent on Type I IFN (IFNαβ) overexpression by myeloid cells in C3H mice (Lochhead et al, ; Ma et al, ; Miller, Ma, Crandall, Wang, & Weis, ; Paquette et al, ) and on Type II IFN (IFNγ) overexpression by T cells in B6 Il10 −/− mice (Sonderegger et al, ; Whiteside et al, ). Conversely, wild‐type C57BL/6 mice, which develop mildly inflammatory LA, have marked upregulation of tissue repair genes in infected joints, with only a modest upregulation of IFN‐responsive genes (Crandall et al, ), similar to our OA cohort or the low inflammatory RA subgroup.…”

“…The altered response to wounding profile was less pronounced and more variable in tissue from patients with RA and other forms of inflammatory arthritis. Only eight of 190 response to wounding genes were differentially expressed between patients with postinfectious LA and other forms of chronic inflammatory arthritis (Figure 4b), and eight were differentially expressed between patients with OA and the other inflammatory arthritides(Figure 4c).2.7 | Dominant interferon response signature inversely correlates with tissue repair signatureIn mice, dysregulated Type I (IFNα/β) or Type II IFN (IFNγ) production is associated with severe LA(Lochhead et al, 2012;Sonderegger et al, 2012;Whiteside et al, 2018). Therefore, Interferome analysis(Rusinova et al, 2013) was performed to identify the percentage of IFN-upregulated genes from those upregulated in LA synovial tissue compared with OA or other forms of chronic inflammatory arthritis (Figure 5a).…”

Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

“…Although wild‐type mice resolve their arthritis with antibiotic therapy, the Il10 −/− mouse model of IFNγ‐dependent LA is the closest equivalent to human postinfectious LA, in which IFNγ, rather than Borrelia infection, appears to play a central role in pathogenesis (Lochhead et al, ). In both Il10 −/− mice (Whiteside et al, ) and patients with postinfectious LA (Lochhead et al, ), IFNγ responses persist or worsen, despite undetectable pathogen loads (Li et al, ). These results suggest that impaired or inadequate IL‐10 responses during and/or after infection may play a role in human postinfectious LA pathogenesis.…”

“…In B. burgdorferi-infected mice, robust IFN responses and suppressed tissue repair responses are found in joints of mouse strains that develop severe LA (Crandall et al, 2006). In particular, Il10 −/− (C57BL/6) mice have a marked Th1 signature and overproduction of arthritogenic IFNγ by T cells Whiteside et al, 2018). This Th1/IFNγ signature is sustained in joints of Il10 −/− mice for up to 18 weeks post infection, when B. burgdorferi are no longer detectible in joint tissue (Whiteside et al, 2018).…”