Context-dependent regulation of cytotoxic T lymphocytes by nuclear receptors

Cytotoxic CD8⁺ T lymphocytes eliminate pathogen-infected and malignant cells through migration to affected tissues, cytokine production, and cytotoxic activity. A mounting body of evidence indicates that CD8 T cell differentiation into functionally different subsets, such as effector, memory, tissue-resident memory, and exhausted T cells, is controlled by a group of nuclear receptors (NRs). NRs sense signals from various physiological and environmental cues, such as nutritional, endocrine, stress/circadian, and metabolic signals, and translate them into gene-regulatory decisions. NRs act through direct and indirect DNA binding, corepressor-coactivator exchange, and transrepression of effector-associated transcription factors, thereby reshaping chromatin accessibility and metabolic programs during CD8 T cell differentiation. This review highlights major CD8 T cell-regulating pathways involving vitamin A-sensing RAR-α, sterol-responsive LXR-β and ROR-α, orphan NR4A proteins; vitamin D receptor (VDR), glucocorticoid receptor (GR), and androgen receptor (AR). Understanding the shared and separable functions of NRs and their ligands provides insights into therapeutic strategies, such as pharmacologic modulation, checkpoint blockade, and chimeric antigen receptor T cell therapies, to promote durable antitumor and antiviral CD8 T cell activities.