Human granzyme B regulatory B cells prevent effector CD4+CD25- T cell proliferation through a mechanism dependent from lymphotoxin alpha

Abstract

IntroductionHuman Granzyme B (GZMB) regulatory B cells (Bregs) have suppressive properties on CD4+ effector T cells by a mechanism partially dependent on GZMB. Moreover, these cells may be easily induced in vitro making them interesting for cell therapy.MethodsWe characterized this population of in vitro induced GZMB+Bregs using single cell transcriptomics. To investigate their regulatory properties, Bregs or total B cells were also co-cultured with T cells and scRNAseq was used to identify receptor ligand interactions and to reveal gene expression changes in the T cells.ResultsWe find that Bregs exhibit a unique set of 149 genes differentially expressed and which are implicated in proliferation, apoptosis, metabolism, and altered antigen presentation capacity consistent with their differentiated B cells profile. Notably, Bregs induced a strong inhibition of T cell genes associated to proliferation, activation, inflammation and apoptosis compared to total B cells. We identified and validated 5 receptor/ligand interactions between Bregs and T cells. Functional analysis using specific inhibitors was used to test their suppressive properties and we identified Lymphotoxin alpha (LTA) as a new and potent Breg ligand implicated in Breg suppressive properties.DiscussionWe report for the first time for a role of LTA in GZMB+Bregs as an enhancer of GZMB expression, and involved in the suppressive properties of GZMB+Bregs in human. The exact mechanism of LTA/GZMB function in this specific subset of Bregs remains to be determined.

Functional significance of DNA methylation: epigenetic insights into Sjögren’s syndrome

“…Mechanistically, LTA operates through two distinct signaling routes. Firstly, as an LTA trimer, it binds to TNF1 and TNF2 receptors, driving lymphangion genesis and elevating the secretion of chemokines and cytokines ( 79 – 82 ). Secondly, it competes with lymphotoxin-β (LTB) to shape a trimeric ligand that binds to the LTB receptor on lymphoid cells and stimulates various pathways, such as NF-KB ( 83 – 85 ).…”

The predictive value of TNF family for pulmonary tuberculosis: a pooled causal effect analysis of multiple datasets

“…GZMB+Bregs inhibit T cell proliferation and effector function by suppressing cytokine production and proliferation. Subsequent administration of LT restores effector T cell proliferation in a dose-dependent manner ( 12 ). The role of LT in the immune response of PTB involves the regulation of B cells and the promotion of T cell proliferation.…”