Author:
Khan Saad,Chakraborty Mainak,Wu Fei,Chen Nan,Wang Tao,Chan Yi Tao,Sayad Azin,Vásquez Juan Diego Sánchez,Kotlyar Max,Nguyen Khiem,Huang Yingxiang,Alibhai Faisal J.,Woo Minna,Li Ren-Ke,Husain Mansoor,Jurisica Igor,Gehring Adam J.,Ohashi Pamela S.,Furman David,Tsai Sue,Winer Shawn,Winer Daniel A.
Abstract
AbstractA dysregulated adaptive immune system is a key feature of aging, and is associated with age-related chronic diseases and mortality. Most notably, aging is linked to a loss in the diversity of the T cell repertoire and expansion of activated inflammatory age-related T cell subsets, though the main drivers of these processes are largely unknown. Here, we find that T cell aging is directly influenced by B cells. Using multiple models of B cell manipulation and single-cell omics, we find B cells to be a major cell type that is largely responsible for the age-related reduction of naive T cells, their associated differentiation towards pathogenic immunosenescent T cell subsets, and for the clonal restriction of their T cell receptor (TCR). Accordingly, we find that these pathogenic shifts can be therapeutically targeted via CD20 monoclonal antibody treatment. Mechanistically, we uncover a new role for insulin receptor signaling in influencing age-related B cell pathogenicity that in turn induces T cell dysfunction and a decline in healthspan parameters. These results establish B cells as a pivotal force contributing to age-associated adaptive immune dysfunction and healthspan outcomes, and suggest new modalities to manage aging and related multi-morbidity.One Sentence SummaryInsulin receptor signaling facilitates the induction of age associated B cell inflammatory changes, which drive phenotypic aging of the T cell compartment and adverse outcomes to mammalian healthspan parameters.
Publisher
Cold Spring Harbor Laboratory