Beyond Exhaustion: The RNA Regulatory Layer of Tissue-Instructed T Cell Dysfunction

CD8⁺ T cell exhaustion is a differentiation program driven by persistent antigen stimulation and stabilized through multiple regulatory layers, including transcription factor networks and chromatin. Beyond these established frameworks, an RNA regulatory layer, encompassing noncoding RNAs, RNA-binding proteins, alternative splicing isoforms, and epitranscriptomic modifications, is emerging as a further determinant of exhausted T cell identity. Retrotransposon-derived transcripts remain largely underexplored in this context, with the exception of LINE1-containing transcripts, which are causally linked to exhaustion and directly therapeutically addressable. Yet, whether this RNA layer is a generalizable feature of exhaustion or is instead instructed by the tissue in which antigen priming occurs remains unknown. Most of the current understanding derives from settings in which naïve CD8⁺ T cells are primed by professional antigen-presenting cells in secondary lymphoid organs. In the liver, however, hepatocytes can prime naïve CD8⁺ T cells directly, generating a hypofunctional state that is transcriptionally and pharmacologically distinct from canonical exhaustion, refractory to checkpoint blockade yet reversible by 4-1BB agonism. We propose that the RNA regulatory layer is a plausible substrate through which tissue-derived signals are encoded, and that the liver offers a powerful model to define and therapeutically target tissue-instructed T cell dysfunction.