Terminal differentiation program of CD8 T cells guides immunotherapeutic options for CLL patients.

In treatment-naive chronic lymphocytic leukemia patients, circulating CD8 T cells accumulate a CD27−CD28−CD57+KLRG1+ terminally differentiated population linked to transient proliferation and poor persistence.

• Why it matters: CLL is incurable and autologous T-cell therapies work in only a minority, while CLL CD8 dysfunction has been attributed to exhaustion despite missing canonical exhaustion markers.
• What they did: The study integrated phenotyping, epigenetic and functional assays on circulating CD8 T cells from treatment-naive CLL patients, identifying senescence-like features and testing responses to repeated activation and CAR T manufacturing steps.
• The result: CD57+ cells showed robust but short-lived effector activity with activation-associated γH2AX signals, impaired persistence, and increased death, and they were incompatible with CAR T manufacturing, but bispecific T-cell engagers enabled effective cytolysis of CLL targets.

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