Work

KLF3: A novel driver of resilient CD8+ T cell cytotoxic programming in chronic infection and cancer 3789

Year: 2025

Type: article

Abstract: Description T cell exhaustion is a major barrier to effective cytotoxic CD8+ T cell immune responses during chronic infections or cancer. Epigenetic silencing of key effector function and memory-related genes reinforces T cell exhaustion, limiting the capacity of CD8+ T cells to sustain durable responses against chronic pathogens or tumors. Therefore, it is crucial to understand the molecular mechanisms that maintain effector function while preventing exhaustion programming in CD8+ T cells. The transcription factor known as Krüppel-like factor 3 (KLF3) is highly expressed in the functional cytolytic subset of CD8+ T cells during chronic viral infection in mice and human cancers. However, its direct role in regulating T cell programming in these settings remains unclear. Our study revealed that antigen-specific, KLF3-overexpressing (OE) CD8+ T cells retain remarkable expression of effector and memory-related programs during chronic LCMV infection in mice, with minimal acquisition of exhaustion-associated epigenetic programs. Furthermore, we found that KLF3-OE tumor-reactive CD8+ T cells demonstrated enhanced cytotoxicity and improved control of solid tumor growth in mice, highlighting its potential as a therapeutic target to boost responses to adoptive T cell therapy for cancer. Our findings reveal a novel role of KLF3 in promoting functional programming of CD8+ T cells during chronic infection and cancer. Funding Sources Supported by NIH R01AI170926; NIH T32AI165391; Ohio State College of Medicine/Comprehensive Cancer Center funding Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1551