Work

CTLA-4 checkpoint signalling modulates germinal centre dynamics and antibody avidity during Borrelia burgdorferi infection in mice.

Year: 2026

Type: preprint

Abstract: 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 from Borrelia-infected mice at days 7 and 14 post-infection, comparing transcriptional profiles with those from mice immunised with heat-killed Borrelia or with a potent germinal centre-inducing protein immunisation. Borrelia infection induced a rapid germinal centre response, however, light zone B cells displayed diminished expression of co-stimulatory and T-B cell interaction molecules while maintaining core germinal centre identity markers, suggesting impaired positive selection. T follicular helper cells upregulated multiple inhibitory checkpoint receptor genes, most prominently Ctla4, alongside an active germinal centre engagement programme. Foxp3? regulatory T cells upregulated genes associated with follicular-homing and suppressive function, including those implicated in CTLA-4-mediated trans-endocytosis. To test whether inhibitory signalling contributes to the impaired humoral response, infected mice were treated with anti-CTLA-4 blocking antibody. CTLA-4 blockade significantly increased plasma cell numbers and enhanced both the magnitude and avidity of Borrelia-specific IgG responses, including the induction of complement-fixing IgG2a. These findings reveal that CTLA-4-dependent inhibitory signalling contributes to defective antibody quality during Borrelia infection, identifying a mechanism by which dysregulated T cell responses may facilitate impaired humoral control of a persistent spirochaetal pathogen.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.30.763258