Aging converts innate B1a cells into potentially pathogenic 4BL cells that induce cytolytic CD8+T cells.

Abstract

Abstract Immune system becomes dysregulated in aging of mammals affecting both myeloid and lymphoid immune cell compartments. Compounded with a life-long antigenic exposure, changes in T cells and increased half-life of mature B cells, conventional B2 cells are enriched for antigen-experienced memory and mature cells at the expense of naive B cells. However, the role of aging on innate B1a cells, the key produces natural antibody to pathogens and endogenous antigens, is not known and is assumed to be negligible. Here, we question this assumption by providing evidence that B1a cells become converted into 4BL cells, the 4-1BBL+MHC class-IHiCD86Hi B cells that induce cytolytic granzyme B (GrB)-expressing CD8+T cells upon aging of humans, macaques and mice 1. This conversion is mediated by aging CD11b+ myeloid cells, which induce a chain of activating events in B1a cells. First, B1a cells express 4-1BBL and IFNgR1 to be used for up regulation of membrane TNFa (mTNFa) and CD86 expression, respectively. Then, using mTNFa, 4BL cells induce GrB expression in CD8+T cells via targeting TNFR2 while providing co-stimulation with CD86. Thus, for the first time, we report that B1a cells become dysregulated upon aging. They lose ability to support tumor growth and gain a new function – the induction of potentially antitumor and autoimmune CD8+T cells. This work was entirely supported by the Intramural Research Program, NIA/NIH.1.