Aging releases the brakes on the T follicular helper cell — B cell axis in murine atherosclerosis 2256916

Abstract

Abstract Introduction Aging is the most dominant risk factor for atherosclerotic cardiovascular disease (ASCVD), which is characterized by the build-up of lipids and immune cells in the arterial wall. Adaptive immune responses play a detrimental role in atherosclerosis development. Studies in young mice have shown that follicular T helper (Tfh) cell responses in secondary lymphoid organs promote B cell differentiation and drive high-affinity antibody production, aggravating atherosclerotic plaque formation. In this study, we aimed to address age-associated changes in the Tfh-B cell axis in atherosclerotic mice. Methods Using flow cytometry we analyzed Tfh and antibody-secreting cells of young (5 months), middle-aged (12 months) and aged (22 months) Ldlr-/- mice. Age-associated changes in Tfh and B cells were further characterized by scRNAseq and scTCR/BCRseq of spleens from young (5 months) and aged (22 months) Ldlr-/- mice. Total and oxidation-specific epitope (OSE) antibody levels were measured in serum. Results Aging was associated with expansion of Tfh (3.8-fold) and Tfr cells (2.9-fold) in lymphoid organs of Ldlr-/- mice. The disproportionate increase in Tfh cells led to a significantly elevated Tfh/Tfr ratio in aged mice. Similarly, scRNAseq revealed age-associated clonal expansion of splenic Tfh cells expressing Pdcd1, Cxcr5, and Bcl6, alongside enhanced expression of Tfh differentiation markers (Ascl2, Il21r), Tfh—B cell interaction genes (Cd40lg), and senescence- (Spp1) and exhaustion-associated (Tigit, Ctla4 and Lag3) genes. In line with these findings, we observed a > 3-fold increase in splenic plasmablast and plasma cells, accompanied by a significant increase in total and OSE-specific IgA, anti-inflammatory IgM, and proinflammatory IgG2b and IgG2c serum levels in aged Ldlr-/- mice. Conclusion In conclusion, aging causes overactivation of the Tfh-B cell axis in atherosclerotic mice. Targeting the Tfh-B cell axis could represent a promising therapeutic strategy to combat atherosclerosis. Funding Source Dutch Heart Foundation, EIC Pathfinder B-specific, AtheroNeth Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)