UC Davis

In response to microbial infection, effector CD4 T cells must polarize appropriately in order to induce an effective inflammatory response that leads to elimination of invading pathogens. Since Borrelia burgdorferi (Bb), the spirochetal agent of Lyme disease, evades immune clearance in infected mice and humans, we wanted to explore the possibility that inappropriate CD4 T cell polarization may contribute to bacterial persistence. In response to Bb infection, CD4 T cell polarization is considered to be Th1 dominant as a result of early Type I IFN production. Additionally, IFNγ producing T cells have been associated with Lyme disease pathology, especially arthritis of the large joints. However, when we stimulated CD4 T cells from Bb infected mice ex vivo with a recombinant form of the Bb surface Ag Arthritis Related Protein (Arp), we were unable to detect the hallmark cytokine produced by Th1 cells, IFNγ. This prompted us to re-examine the polarization state of effector CD4 T cells throughout Bb infection by quantitative RT-PCR and flow cytometry. We were surprised to find only modest Th1 polarization as measured by expression of the Th1 lineage defining transcription factor, Tbet (Tbx21), and little to no induction of Ifng. This could not be explained by enhanced polarization to two other major T helper lineages, Th2 or Th17. Nor could it be explained by the migration of polarized CD4 T cells to a T cell effector site, the skin, as skin resident T cells also failed to polarize. Furthermore, we did not observe enhanced effector polarization in Arp-specific CD4 T cells, as identified by a novel I-Ab tetramer. Instead, Arp-specific CD4 T cells were skewed toward a T follicular helper (Tfh) phenotype, which provides the first direct evidence that antigen specific Tfh are generated in response to Bb infection. Our data support the hypothesis that Bb induces suboptimal CD4 T cell polarization, thus we propose effector CD4 T cell polarization as a novel target of Bb immune evasion.