Dynamics of the T follicular helper response in Borrelia burgdorferi infection

Abstract

Borrelia burgdorferi (Bb), the bacterial agent of Lyme disease, has evolved numerous immune evasion mechanisms that result in Bb persistence in mice, its natural host, following infection via tick-bite. IgG antibodies control Bb-tissue loads but cannot clear the infection. We previously observed abnormalities in T-dependent B cell responses in mice following infection. Specifically, we demonstrated premature germinal center (GC) collapse, a lack of affinity maturation, memory B cell and long-lived plasma cell responses, and Ig responses that were skewed toward IgM. Due to the central role of CD4+ follicular T helper (TFH) cells in initiating and maintaining GCs, we hypothesized that Bb infection causes TFH dysfunction. Since Bb-specific CD4 T cell responses have not previously been characterized, we first identified an I-Ab restricted epitope on Arthritis related protein (Arp) of Bb, and used tetramers to characterize these Bb-specific CD4 T cells by FACS. We observed a surprisingly robust induction of Arp-specific TFH by day 14 of infection, which was followed by a precipitous decline in total and Arp-specific TFH by day 21 that preceded the observed collapse of GC. In order to explain this sharp TFH decline we studied the expression of inhibitory receptors on TFH. We also followed the induction of FOXP3+ regulatory T follicular (TFR) cells, which are known to limit GC responses. Not only were we able to demonstrate induction of a significant population of TFR, we also found that expression of the inhibitory Programmed death receptor 1 (PD-1) was significantly higher on Arp-specific TFH compared to overall TFH. Our data suggest that overshooting TFH regulatory mechanisms may inhibit T-dependent B cell responses during Bb infection.