PD-1⁺ CD8⁺ T cells: roles of PD-1 beyond an exhaustion marker

Programmed cell death protein 1 (PD-1) has long been considered a central molecule in CD8⁺ T cell exhaustion and immunosuppression. However, recent studies have revealed that PD-1⁺CD8⁺ T cells are not a homogeneous population of terminally dysfunctional cells, but rather constitute key immune cells with significant heterogeneity and functional plasticity within tissue immune microenvironments. PD-1 signaling operates throughout multiple stages of CD8⁺ T cell biology, including thymic development, peripheral activation, chronic antigen stimulation, and tissue residency. By finely regulating T cell receptors (TCRs) signal strength, metabolic state, and transcriptional programs, it deeply participates in cell fate decisions while limiting immunopathology. In chronic infections and tumors, persistent antigen stimulation drives PD-1⁺CD8⁺ T cells to form an exhaustion lineage with a defined differentiation hierarchy, encompassing stem-like precursor cells, effector-like transitional cells, and terminally exhausted cells. PD-1 is not only a characteristic marker of this lineage but also a critical regulatory node through which immune checkpoint blockade therapy exerts its therapeutic effects. Furthermore, in contexts such as tissue-resident memory T cells (T_RM), GZMK⁺CD8⁺ T cells, and other disease-associated microenvironments, sustained PD-1 expression often represents an adaptive functional regulatory state rather than mere functional inhibition. This review explores the multidimensional regulatory roles of PD-1 in CD8⁺ T cells, with a focus on elucidating the diverse functions and clinical significance of PD-1⁺CD8⁺ T cells in cancer, chronic infections, and autoimmune diseases.