Lymphocyte-derived cholinergic circuits modulate germinal center output and B cell activation.

Nat Immunol 2026

Nechanitzky D, Smith LK, Nechanitzky R, Jafari SM, Haight J et al.

Abstract

Germinal centers (GCs) are specialized lymphoid structures in which activated B cells undergo clonal selection and B cell receptor (BCR) somatic hypermutation to generate high-affinity antibodies. Previous work has shown that T cells expressing choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh), are linked to the production of high-affinity antibodies in the GC response. However, whether B cells in the GC also express ChAT, and the details of the interplay of cholinergic circuits within the GC, remain unclear. Here we show that Chat expressed by GC B cells contributes to the early accumulation of high-affinity GC B cells following antigen encounter. We identify key transcriptional regulators of Chat expression in GC B cells and demonstrate that ACh receptor (AChR) expression is dynamically coordinated during B cell activation. In vitro, we show that ACh binding to muscarinic AChRs limits plasma cell differentiation and dampens BCR signal transduction to fine-tune the threshold for affinity-based positive selection. Together, these findings reveal a previously unrecognized regulatory axis that operates early during GC selection and uses cholinergic signals to shape B cell fate decisions and humoral immunity.

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