Follicular B cells from old mice are hyper-responsive and produce non-specific antibodies.

Abstract

Immunosenescence is the increase in immune defects that occurs during aging. To identify any intrinsic defects in old B lymphocytes, we devised a transfer system to introduce follicular B cells from old mice (FOO, >22 months) or young mice (FOY, 8–12 weeks) into young mMT mice which have no B cells. Using this system, we observed that, compared to FOY cells, FOO cells do not produce antigen-specific antibodies to nitrophenyl (NP)-chicken gamma globulin after immunization. Examination of the germinal center (GC) response shows that FOO cells produced increased numbers of GC B cells which have divided faster than their FOY counterparts, but they have significantly decreased NP+ λ+ antigen-specificity. To understand the differences between FOO and FOY cells, single-cell RNAseq was performed on naïve and day 14 GC B cells. Comparing naïve populations revealed very few differences with only 387 differentially expressed genes between FOO and FOY cells. Interestingly, Ccr6 was upregulated in the FOO cells, suggesting that the cells were pre-activated before transfer into mMT mice. Antibody repertoire analysis also confirmed the lack of antigen-specificity in FOO cells, as the canonical NP-specific IgH V-gene, 1–72, was utilized in fewer cells and had zero instances of the CDR2 W33L mutation known to increase affinity. Taken together, old mice produce B cells which are pre-activated and hyper-responsive upon immunization, causing a lack of proper selection and affinity maturation in the GC. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.