IL-15–Driven NK-like Activation Is Augmented in Senescent CD57+CD8+ Memory T Cells

Introduction/Rationale: IL-15 can stimulate CD8+ memory T (Tm) cells to exert NKG2D-mediated NK-like cytotoxicity in a TCR-independent manner, which can contribute to immunopathological host injury during viral infections. However, it has not been fully elucidated if senescent status of CD8+ Tm cells determines the degree of IL-15–induced NK-like activation. Here, we examined IL-15 responsiveness of replicative-senescent CD57+CD8+ Tm cells compared to CD57-CD8+ Tm cells and investigated the underlying molecular mechanism.

Methods: We obtained PBMCs from healthy donors (20-74 years) and analyzed CD57+CD8+ and CD57-CD8+ Tm cells by flow cytometry and bulk RNA-seq following ex vivo IL-15 stimulation. In addition, we performed single nucleus-multiome analysis (snRNA/ATAC-seq) of CD57+CD8+ and CD57-CD8+ Tm cells. We further analyzed single-cell transcriptomes of bystander CD8+ T cells identified with dCODE MHC-I multimers from PBMCs of patients with acute HAV infection.

Results: We demonstrated that senescent CD57+CD8+ Tm cells exhibit augmented IL-15–induced NK-like activation compared to non-senescent CD57-CD8+ Tm cells. The degree of IL-15–induced NK-like cytotoxicity was correlated with age and the proportion of CD57+CD8+ Tm cells. Furthermore, CD57+CD8+ Tm cells exhibited stronger NK-like activation than CD57- counterparts in patients with acute HAV infection, where the NK-like bystander activation of memory CD8+ T cells is well-exemplified. Notably, CD57+CD8+ Tm cells exhibited upregulation of Aiolos, known as a key regulator of AP-1 that is critical for IL-15–induced NK-like activation of CD8+ Tm cells.

Conclusion: Our findings reveal a mechanism by which augmented IL-15–induced NK-like activation of senescent CD57+CD8+ Tm cells is associated with enhanced bystander activation of CD8+ T cells in the elderly, providing insights for novel molecular targets for the treatment of aging-associated immunopathology.