Haploidentical Hematopoietic Stem Cell Transplantation Drives Time-dependent premature T Cell Senescence: Recipient...

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) cures hematological malignancies but severely impairs long-term immune reconstitution by inducing T cell senescence. Previous studies have linked anti-tumor therapy to immune aging; however, it remains unclear whether haploidentical HSCT (haplo-HSCT) independently drives progressive premature T cell senescence beyond pre-transplant chemotherapy, and how the recipient microenvironment shapes donor T cell aging patterns. This study aimed to determine the independent effect of haplo-HSCT on time-dependent T cell senescence and to elucidate the bidirectional regulatory role of recipient age-associated microenvironments on phenotypic and molecular aging signatures of donor-derived T cells. A total of 34 subjects were enrolled, including 24 haplo-HSCT recipients stratified by post-transplant duration (<12 months, n = 12; ≥12 months, n = 12) and 10 patients receiving chemotherapy alone. Eighteen age-reciprocal donor-recipient pairs were analyzed. Multiparameter flow cytometry, multiplex cytokine assay, SASP PCR array, epigenetic clock profiling, and telomere length measurement were performed to comprehensively characterize T cell senescence features. Haplo-HSCT induced robust, time-dependent senescence in both CD4⁺ and CD8⁺ T cells, accompanied by substantial T cell subset remodeling. This included a reduced CD4/CD8 ratio, contracted naive and central memory T cell compartments, and expansion of senescence-prone terminal effector memory T cells, which was particularly pronounced in the CD8⁺ compartment. Terminal senescent CD27⁻CD28⁻CD57⁺ T cells (both CD4⁺ and CD8⁺) from long-term recipients exhibited significantly upregulated canonical senescence molecules p16^INK4a and γH2AX, providing solid molecular evidence for transplant-associated T cell senescence. In contrast, chemotherapy alone failed to induce comparable terminal T cell senescence phenotypes. Haplo-HSCT further established persistent peripheral inflammatory imbalance and remodeled the prosenescent SASP transcriptional profile of circulating T cells. Notably, recipient age exerted bidirectional modulation of donor T cell epigenetic aging, telomere homeostasis, and SASP remodeling. Haplo-HSCT serves as an independent, time-dependent driver of premature donor T cell senescence, distinct from chemotherapy-induced immune alteration. The recipient age-related microenvironment is a critical regulator of donor T cell epigenetic aging, telomere maintenance and SASP reprogramming. This study systematically delineates multi-layered signatures of post-transplant T cell senescence and provides a theoretical foundation for developing age-adapted strategies to improve long-term immune reconstitution after haplo-HSCT.