The evolution of T cell stemness in chronic viral infections

Persistent viral infections pose a unique challenge to the immune system. Prolonged antigen exposure drives T cells into a state of exhaustion — a progressive loss of effector function that undermines viral clearance. Over the past two decades, research has revealed that exhausted T cell populations are not uniform. Within them sits a distinct subset with stem-like properties: the capacity for self-renewal, multipotency, and the ability to regenerate more differentiated progeny. Initial insights came largely from the lymphocytic choriomeningitis virus (LCMV) mouse model, which established much of the conceptual and experimental groundwork for the field. These stem-like T cells — marked by transcription factors such as TCF1 — have since been identified across chronic human infections including HIV and HCV, positioning T cell stemness as a central pillar of modern immunology.Despite rapid progress, critical gaps remain in our understanding of how T cell stemness is established, maintained, and lost during chronic viral infection. The transcriptional and epigenetic programs that govern self-renewal in both CD4⁺ and CD8⁺ stem-like populations are incompletely defined, and the functional relationship between these two subsets remains underexplored. Parallels between T cell exhaustion in chronic infection and dysfunctional T cell states in cancer and autoimmunity offer rich ground for comparative investigation, yet a unified mechanistic framework has yet to emerge.Recent methodological advances — particularly single-cell RNA sequencing and gene set enrichment analysis — have transformed our ability to dissect T cell heterogeneity at resolution that bulk approaches simply could not achieve. This Research Topic aims to synthesize historical milestones with cutting-edge findings, tracing the intellectual arc from foundational LCMV studies to current debates around progenitor identity, lineage commitment, and therapeutic exploitation of stem-like T cells in disease settings.We invite original research articles, reviews, and perspective pieces that address the biology of stem-like T cells in the context of chronic viral infection and related disease states. Relevant themes include, but are not limited to:• The identification and characterization of stem-like CD4⁺ and CD8⁺ T cell subsets during chronic infection• Molecular mechanisms of T cell self-renewal and differentiation, including transcriptional regulators (e.g., TCF1, TOX, BATF) and epigenetic remodeling• Lessons from the LCMV model and their translation to human chronic viral infections• Parallels between exhaustion in chronic infection, cancer, and autoimmunity• Single-cell RNA sequencing, ATAC-seq, and gene set enrichment approaches applied to T cell stemness• Therapeutic strategies targeting stem-like T cell populations to restore immunitySubmissions that bridge historical context with contemporary findings are particularly encouraged. Topic editors: Vikas Duhan, Piyush Sharma, Linda Bradley, Vijayakumar Velu Source: https://www.frontiersin.org/research-topics/78512/the-evolution-of-t-cell-stemness-in-chronic-viral-infections