W132 - Human Regulatory B Cells Prevent Effector CD4+CD25- t Cell Proliferation Through a Mechanism Dependent from Granzyme B and Lymphotoxin Alpha

Hoa Le Mai; Amandine Dupuy; Gaëlle Tilly; Martin Braud; Cynthia Fourgeux; Magali Giral; Jean-Michel Robert; Nicolas Degauque; Richard Danger; Jérémie Poschmann; Sophie Brouard

Abstract Text: Human 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. Our aim was to study their profile, role and interactions in regard with their mechanisms of suppression in scRNAseq performed on induced Bregs, non-Bregs and T cells after coculture. Predicted receptor/ligand interactions on Bregs suppressive properties were then assessed by functional analysis. Bregs exhibit a profile of 149 highly differentially expressed genes, mainly associated with cell proliferation, apoptosis, metabolism, and altered antigen presentation capacity consistent with their differentiated B cells profile. When cocultured with Bregs, T cells display strong inhibition of genes of proliferation, activation, inflammation and apoptosis. T cells/Bregs interaction analysis evidenced Lymphotoxin alpha (LTA) as a key Breg ligand. LTA and GZMB are regulated by common transcription factors CREM directly modulated by LTA and BATF downstream IL-21. Finally, we demonstrated that LTA is involved in GZMB+Bregs suppressive properties with Pateclizumab, an LTA inhibitor, preventing their function. These data are the first to report on a role of LTA in the suppressive properties of Bregs as an up-stream enhancer of GZMB.