Ineffective polarization characterizes CD4 T cell responses to persistent Borrelia burgdorferi infection

Abstract Borrelia burgdorferi (Bb), the spirochetal agent of Lyme disease, evades immune clearance in infected mice and humans, suggesting ongoing immune suppression. Here we explored the functionality of Bb-induced CD4 T cell responses in infected mice, which are considered Th1 polarized. Surprisingly, in vitro restimulation of CD4 T cells from mice infected for 12 days failed to induce secretion of the hallmark Th1 cytokine IFNg. Consistent with that data, flow cytometry and RNAseq of CD4 T cells from lymph nodes (LNs) of Bb-infected mice at 6, 10, 14, and 21 days post infection (dpi) showed a transient Th1 and Th17 polarization that peaked at 10 dpi before declining, confirmed also by RT-PCR. While Th1 and Th17 gene expression profiles returned to baseline by 14 dpi, increased frequencies of CXCR4+ CXCR5+ PD-1 hiICOS+ BCL6+ T follicular helper (Tfh) cells emerged at that time, concomitant with germinal center induction. The lack of CD4 T cell effector polarization was noted also in the skin, an effector site after Bb infection, as well as in antigen-specific T cells, which were identified using a new MHCII tetramer to the Bb surface antigen arthritis related protein (Arp). Together, our results indicate a failure to sustain effector CD4 T cell polarization after Bb infection, identifying CD4 T cells as a potential target of Bb-mediated immune suppression. This work was supported by grants from the Global Lyme Alliance, the Stephen & Alexander Cohen Foundation, NIH R01AI157007 (NB) and T32 AI060555 (EMH). This work was supported by grants from the Global Lyme Alliance, the Stephen & Alexander Cohen Foundation, NIH R01AI157007 (NB) and T32 AI060555 (EMH).