Abstract
CD5 and CD6 are signal transducing type I transmembrane scavenger receptors mediating recogni-tion of host and microbial ligands. They are mainly expressed by all T cells, but also a small subset of B cells for which limited information is still available. Here we evaluated the impact of CD5 and CD6 deficiency on B1 and innate-like B cell populations in spleen and peritoneum compared to wild-type BL6 mice and Btk-deficient CBA/N mice. Both CD5- (Cd5-/-) and CD6 (Cd6-/-)-deficient mice showed decreased B1 cells (B220loCD11b+) in the spleen, as well as in peritoneal exudate. By contrast, B220loCD11b- (B220lo) cells were reduced in Cd5-/- mice from the neonatal stage, while remaining similar to BL6 levels in Cd6-/- mice. Transcriptomic analysis of purified B220lo cells revealed a con-served core program across wild-type, Cd5-/- and Cd6-/- strains, with reduced BCR co-receptor and Ras signalling, alongside increased pathways related to activation, transcriptional regulation, and im-mune modulation. Genotype-specific divergences were found, consisting of CD5 deficiency pro-moting a more structured and regulated signalling state, while CD6 deficiency induced a highly activated and metabolically reprogrammed phenotype, with increased mitochondrial activity, redox balance, biosynthetic capacity and reduced dependence on interferon-mediated signalling. Collec-tively, these findings identify B220lo B cells as a flexible population whose functional polarization is differentially controlled by CD5- and CD6-dependent regulatory axes governing signalling organi-zation and metabolic activation.