A stem-like CD8+ T cell reservoir resists exhaustion and sustains alloimmunity a decade after transplantation

Abstract Chronic antigen exposure is commonly thought to drive CD8 + T cells toward exhaustion. However, in transplantation, we show that sustained immunity is maintained by a persistent stem-like reservoir that iteratively replenishes short-lived cytotoxic effectors rather than progressing toward exhaustion. Analysis of rejected human kidney allografts obtained approximately 10 years after transplantation reveals extensive overlap of CD8 + T-cell clonotypes between the circulation and allografts. These clones are maintained in a TCF1 + stem-like state in the circulation but differentiate into TCF1 − cytotoxic effectors within allografts. Mouse models demonstrate that cytotoxic effector differentiation is restrained by TCF1 and depends on lactate dehydrogenase A. Cytotoxic effectors are short-lived and insufficient to mediate allograft rejection upon transfer into secondary hosts, whereas stem-like T cells retain self-renewal capacity, continuously replenish cytotoxic effectors, and drive rejection across serial transplantations. These findings establish a principle whereby a stem-like CD8 + T-cell reservoir drives sustained alloimmunity through continuous effector differentiation.