TLR2 Is a Negative Regulator of Th17 Cells and Tissue Pathology in a Pulmonary Model of Fungal Infection

Abstract

To study the role of TLR2 in a experimental model of chronic pulmonary infection, TLR2-deficient and wild-type mice were intratracheally infected with Paracoccidioides brasiliensis, a primary fungal pathogen. Compared with control, TLR2−/− mice developed a less severe pulmonary infection and decreased NO synthesis. Equivalent results were detected with in vitro-infected macrophages. Unexpectedly, despite the differences in fungal loads both mouse strains showed equivalent survival times and severe pulmonary inflammatory reactions. Studies on lung-infiltrating leukocytes of TLR2−/− mice demonstrated an increased presence of polymorphonuclear neutrophils that control fungal loads but were associated with diminished numbers of activated CD4+ and CD8+ T lymphocytes. TLR2 deficiency leads to minor differences in the levels of pulmonary type 1 and type 2 cytokines, but results in increased production of KC, a CXC chemokine involved in neutrophils chemotaxis, as well as TGF-β, IL-6, IL-23, and IL-17 skewing T cell immunity to a Th17 pattern. In addition, the preferential Th17 immunity of TLR2−/− mice was associated with impaired expansion of regulatory CD4+CD25+FoxP3+ T cells. This is the first study to show that TLR2 activation controls innate and adaptive immunity to P. brasiliensis infection. TLR2 deficiency results in increased Th17 immunity associated with diminished expansion of regulatory T cells and increased lung pathology due to unrestrained inflammatory reactions.

TLR2-Mediated Production of IL-27 and Chemokines by Respiratory Epithelial Cells Promotes Bleomycin-Induced Pulmonary Fibrosis in Mice

“…However, the regulatory effects of TLR2 on Th17 cells have appeared to be contradictory in various studies. In pulmonary fungal infection and brain abscess, TLR2 was reported to act as a negative regulator for Th17 cells (24,37), whereas in experimental autoimmune encephalomyelitis, skin inflammation, and tuberculosis infection, TLR2 was reported to have the opposite effect (38)(39)(40). These findings suggest that the specific effect of TLR2 on Th17 cells varies with the type of immune response and depends on the microenvironment of the target tissues.…”

“…In several in vivo studies, TLR2 has been demonstrated to control the expansion and function of T reg cells (21)(22)(23), which inhibit Th17 cells via TLR2 signals in a pulmonary fungal infection model system (24). These findings led us to hypothesize that the TLR2-dependent expansion of T reg cells might inhibit Th17 cells in the BIPF model.…”

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

“…In a murine model of S. aureus brain abscess, TLR2 deficiency was associated with the increased infiltration of IL-17 producing T cells to the lesions [24]. Similarly, in Paracoccidioides brasiliensis infection of the lung, TLR2 À/À mice displayed a Th17 phenotype that was associated with impaired expansion of regulatory CD4 1 CD25 1 Foxp3 1 T cells [25]. In contrast, the TLR2 ligand Pam 3 CSK 4 was shown to directly induce the production of IL-17 by gdT cells [26].…”

TLR2 Engagement on Dendritic Cells Promotes High Frequency Effector and Memory CD4 T Cell Responses

“…By contrast, TLR2 engagement was shown to favor Th2 responses in some cases (19), to promote IFN-␥ production in other studies (20), and has been shown to promote IL-10 production and enhance Treg activity in vivo (21). TLR2 has been shown to also regulate IL-17 production; however, different infection models have shown either enhancing (22,23) or inhibitory effects (24,25), and its direct effect on IL-17 production by Ag-specific T cells is not clear. Therefore, the role of TLR2 engagement in driving the differentiation of CD4 T cells during priming in vivo remains an unresolved issue.…”

“…TLR2 expression was also found to promote IL-17 production in human CD4 T cells (22), consistent with our results here. However, in infection models, TLR2 deficiency has been associated with increased IL-17 production in inflammatory sites (24,25), suggesting that other influences of inflammation and infection may affect how different TLR control T cell responses. TLR2 engagement has also been associated with increased Treg expansion in vivo (20,33,46,54), although this TLR2-mediated effect was due to direct ligation of TLR2 on Tregs (20,33).…”