Ineffective CD4 T cell polarization reveals a novel immune evasion target of Borrelia burgdorferi

Abstract

Appropriate polarization of effector CD4 T cells is essential for eliminating invading pathogens. Borrelia burgdorferi (Bb), the spirochetal agent of Lyme disease, evades immune clearance in infected mice and humans, establishing bacterial persistence. Here we aimed to explore the functionality of CD4 T cell as a possible target of Borrelia-induced immune evasion. In response to Bb infection, CD4 T cell polarization is considered to be Th1 dominant. However, when we stimulated CD4 T cells from Bb infected mice ex vivo with Bb surface Ag Arthritis Related Protein (Arp), we were unable to detect IFNγ, prompting us to re-examine the polarization state of lymph node and blood effector CD4 T cells throughout Bb infection by quantitative RT-PCR and flow cytometry. In contrast to prevailing views, we found only modest numbers of Th1-polarized activated CD4 T cells, as measured by expression of Tbet (Tbx21), and little to no induction of Ifng, including in Bb-specific CD4 T cells, identified by a novel I-Ab tetramer to Arp. This could not be explained by enhanced polarization to Th2 or Th17, as GATA-3 and RORγt expression were also largely absent. Nor could it be explained by polarization at a T cell effector site, the skin, as skin-resident T cells also showed no polarization even 4 months after infection. Furthermore, Th1 polarization was not necessary for controlling bacterial dissemination, as Bb infection of Tbet−/− mice showed significant reductions in Borrelia numbers in the tibiotarsal joints, which correlated with enhanced Th17 polarization as measured by RORγt expression. Together, our data demonstrate a failure of CD4 T cell polarization after Bb infection, indicating effector CD4 T cell polarization as a novel target of Bb immune evasion.