Nonlinear Aging of the Human TCR Repertoire Is Influenced by Sex, CMV, and Cancer

Aging is accompanied by a progressive decline in immune function, increasing susceptibility to infections, cancer, and poorer treatment outcomes. The diversity of the T cell receptor (TCR) repertoire, reflecting the capacity to recognize diverse antigens, is known to decline with age. However, how intrinsic and extrinsic factors jointly shape TCR diversity and its rate of decline, as well as the extent to which this diversity influences clinical outcomes in cancer, remain poorly characterized. Here, we integrate TCR sequencing data from 1.32 billion unique T cell clones, derived from 798 patients with cancer and 5052 individuals without cancer across 14 independent cohorts, to systematically characterize the effects of age, sex, and chronic cytomegalovirus (CMV) infection on peripheral blood repertoire diversity. We identify a nonlinear trajectory of diversity loss that accelerates after midlife, with a marked increase in the rate of decline beyond approximately 50 years of age, which is further modified by sex and CMV infection. In patients with cancer, higher peripheral TCR diversity was associated with improved overall survival across multiple cancer types, even when accounting for the impact of age, sex, and CMV on diversity. Together, these findings underline peripheral TCR repertoire diversity as a dynamic marker of immune aging shaped by demographic and chronic viral factors.