T Cells Exacerbate Lyme Borreliosis in TLR2-Deficient Mice

Abstract

Infection of humans with the spirochete, Borrelia burgdorferi, causes Lyme borreliosis and can lead to clinical manifestations such as arthritis, carditis, and neurological conditions. Experimental infection of mice recapitulates many of these symptoms and serves as a model system for the investigation of disease pathogenesis and immunity. Innate immunity is known to drive the development of Lyme arthritis and carditis, but the mechanisms driving this response remain unclear. Innate immune cells recognize B. burgdorferi surface lipoproteins primarily via toll-like receptor (TLR)2; however, previous work has demonstrated TLR2−/− mice had exacerbated disease and increased bacterial burden. We demonstrate increased CD4 and CD8 T cell infiltrates in B. burgdorferi-infected joints and hearts of C3H TLR2−/− mice. In vivo depletion of either CD4 or CD8 T cells reduced Borrelia-induced joint swelling and lowered tissue spirochete burden, whereas depletion of CD8 T cells alone reduced disease severity scores. Exacerbation of Lyme arthritis correlated with increased production of CXCL9 by synoviocytes, and this was reduced with CD8 T cell depletion. These results demonstrate T cells can exacerbate Lyme disease pathogenesis and prolong disease resolution possibly through dysregulation of inflammatory responses and inhibition of bacterial clearance.

A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis

“…These T cells, in turn, enhanced mononuclear cell migration via the increased release of other inflammatory factors . A recent study in C3H/HeN mice showed that this increase may be attributed to CD8 T‐cell activation of synoviocytes . Moreover, transcripts for the IFN‐inducible gene IFN‐γ‐induced GTPase were elevated .…”

“…The number of T cells attracted to the joint tissue was enhanced, possibly through augmented production of T‐cell chemokines CXCL9 and CXCL10. These T cells, in turn, enhanced mononuclear cell migration via the increased release of other inflammatory factors . A recent study in C3H/HeN mice showed that this increase may be attributed to CD8 T‐cell activation of synoviocytes .…”

“…TLR2-deficient mice were shown to have a significant increase in the number of spirochetes in their joints after infection compared to WT mice. 157 170,171 A recent study in C3H/HeN mice showed that this increase may be attributed to CD8 T-cell activation of synoviocytes. 171 Moreover, transcripts for the IFN-inducible gene IFN-γ-induced GTPase were elevated.…”

“…157 170,171 A recent study in C3H/HeN mice showed that this increase may be attributed to CD8 T-cell activation of synoviocytes. 171 Moreover, transcripts for the IFN-inducible gene IFN-γ-induced GTPase were elevated. 170 Intriguingly, recent studies have shown that TLR2 can function as a co-receptor on activated T cells, influencing their responses and function.…”

Spirochetal Lipoproteins and Immune Evasion

“…TLR signaling leads to increased production of numerous cytokines that induce pro-inflammatory responses (25, 47). Interestingly, TLR-deficient mice had exacerbated inflammation and increased spirochetal burdens, both of which were attenuated by impairing T cell responses (70). As a bodily response to the vast amounts of pro-inflammatory cytokines produced upon spirochetal lipoprotein presence, monocytes have also been seen to produce IL-10 upon being presented with B. burgdorferi lipoproteins (71–75).…”