CTLA-4 checkpoint signalling modulates germinal centre dynamics and antibody avidity during Borrelia burgdorferi infection in mice.
Borrelia burgdorferi, the causative agent of Lyme borreliosis, persists in mammalian hosts despite robust activation of innate and adaptive immunity. A hallmark of murine infection is the production of low-avidity antibodies, yet the immunological mechanisms underlying this defective humoral response remain poorly understood. Here, we used single-cell RNA sequencing of draining lymph node cells…
The research investigates the role of CTLA-4 checkpoint signalling in the immune response to Borrelia burgdorferi, the bacterium responsible for Lyme borreliosis. The study used single-cell RNA sequencing to examine lymph node cells from mice infected with Borrelia at different time points, comparing their transcriptional profiles to those from mice that received heat-killed Borrelia or potent germinal centre-inducing protein immunisation.
The findings suggest that while Borrelia infection triggers a rapid germinal centre response, B cells in the light zone display impaired positive selection, characterized by reduced expression of co-stimulatory and T-B cell interaction molecules while retaining core germinal centre identity markers. Notably, T follicular helper cells upregulate inhibitory checkpoint receptor genes, particularly Ctla4, concurrent with an active germinal centre engagement programme.
Additionally, regulatory T cells express genes associated with follicular-homing and suppressive function, including those implicated in CTLA-4-mediated trans-endocytosis. The researchers tested whether inhibitory signalling contributes to the defective humoral response by administering an anti-CTLA-4 blocking antibody to infected mice.
The results indicate that CTLA-4 blockade significantly elevates plasma cell numbers and enhances both the magnitude and avidity of Borrelia-specific IgG responses. This includes the induction of complement-fixing IgG2a, suggesting that CTLA-4-dependent inhibitory signalling plays a crucial role in defective antibody quality during Borrelia infection.
The study provides insight into a mechanism whereby dysregulated T cell responses may facilitate impaired humoral control of a persistent spirochaetal pathogen.
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