T cells are essential players in immune regulation and defense. However, in chronic disease settings—including persistent viral infections, tumors, and neurodegenerative disorders—their roles often become dysregulated. Dysfunctional T cell states such as exhaustion, immune escape, and maladaptive plasticity are now recognized as critical drivers of disease progression across otherwise distinct pathological conditions.

Despite the differences in tissue microenvironments and disease origins, these chronic conditions share immunological features—including altered antigen presentation, sustained inflammation, and persistent antigen exposure—that shape T cell fate. Understanding the common molecular and cellular mechanisms behind T cell dysfunction offers a unique opportunity to uncover converging therapeutic strategies.

This Research Topic aims to explore how T cell exhaustion, reprogramming, and dysfunction manifest across chronic disease contexts. We encourage contributions that take an integrated, mechanistic, or translational approach to dissect T cell behavior in immune-stressed environments. Special emphasis will be placed on work that uncovers shared regulatory pathways, identifies biomarkers of dysfunction, or leverages advanced technologies to study T cell fate and function.

Areas of interest include, but are not limited to:

-Mechanisms of T cell exhaustion in chronic infections and tumors
-Epigenetic and metabolic reprogramming of T cells in persistent immune activation
-T cell-mediated neuroinflammation and maladaptive plasticity in neurodegeneration
-Immune privilege and immune escape in CNS and tumor microenvironments
-Influence of antigen presentation and co-signaling (co-stimulatory/co-inhibitory) on T cell fate
-Use of single-cell RNA-seq, spatial transcriptomics, and TCR repertoire profiling
-Multi-omics integration (genomics, epigenomics, proteomics, metabolomics) to define dysfunctional T cell states
-Systems immunology approaches to map T cell regulation across chronic diseases
-Role of non-coding RNAs, RNA modifications, and chromatin architecture in T cell dysfunction
-Identification of antigen-specific T cell responses and clonal evolution in chronic disease models

We welcome original research, reviews, and perspectives focused on T cell biology in chronic diseases. Translational studies and those using cutting-edge techniques, animal models, or integrative approaches are particularly encouraged. Contributions that bridge disease areas and reveal cross-cutting mechanisms of T cell dysfunction will be especially valuable in fostering a unified understanding and advancing T cell-targeted therapies.

The Topic Editors declare no Conflicts of Interest

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T Cells at the Crossroads of Viral Infections, CNS Inflammations, and Cancer: Guardians or Culprits?

Topic Coordinators