B cells drive CD4 T cell immunosenescence and age-associated health decline

Dysregulation of the adaptive immune system is a key feature of aging and is associated with age-related chronic diseases and mortality. Here, we find that T cell aging, especially in the CD4 subset, is controlled by B cells. B cells contributed to the age-related reduction of naive CD4 T cells, their differentiation toward immunosenescent T cell subsets, and age-associated T cell receptor clonal restriction. Concurrently, mice lacking B cells displayed improvements in health span and life span. We uncovered a role for B cell-intrinsic insulin receptor signaling in influencing age-related B cell phenotypes that in turn induces CD4 T cell dysfunction, a process that is in part driven by major histocompatibility complex class II. These results identify B cells as critical mediators driving age-associated adaptive immune dysfunction and health-span outcomes and suggest previously unrecognized modalities to manage aging and related health decline.