Research Article: NOSIP overexpression promotes long-term persistence of CD8 + T cells during chronic infection
Abstract:
Chronic antigen exposure drives CD8 + T cell exhaustion; however, strategies to maintain a long-lived, functional CD8 + T cell population under chronic stimulation remain unclear. In this study, we demonstrate that overexpression of nitric oxide synthase–interacting protein (NOSIP) enhances the persistence of antigen-specific CD8 + T cells under chronic antigen stimulation. Notably, NOSIP overexpression preserved a less differentiated CX3CR1 neg subset and inhibited its progression toward an apoptosis-prone CX3CR1 hi state, which was associated with reducing cell death and promoting long-term persistence. In a tumor model, NOSIP-overexpressing CD8 + T cells exhibited improved tumor control, indicating that NOSIP-mediated persistence confers superior antitumor capacity. Furthermore, NOSIP overexpression increased the responsiveness of CD8 + T cells to programmed death-ligand 1 blockade, suggesting that NOSIP may represent a promising therapeutic target.
Introduction:
During chronic viral infections and tumor progression, persistent antigen stimulation induces CD8 + T cell exhaustion, which is characterized by impaired effector functions, upregulation of immune checkpoint molecules, and increased apoptosis, ultimately resulting in inadequate long-term host protection ( 1 , 2 ). Exhausted CD8 + T cells are heterogeneous and comprise two major subsets: progenitor-exhausted and terminally exhausted cells ( 3 , 4 ). While progenitor-exhausted cells retain proliferative capacity and…
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