CD8⁺ T cell heterogeneity and function in lupus nephritis: a focused review

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus marked by immune complex deposition and tissue-specific inflammation. Advances in single-cell transcriptomics and high-dimensional immune profiling have revealed that CD8⁺ T cells form a highly heterogeneous and compartment-dependent landscape across peripheral blood, kidney, and urine. This review aims to delineate how compartment-specific phenotypes and signaling programs of CD8⁺ T cells collectively shape the immunopathogenesis of lupus nephritis (LN). We synthesize current evidence into a unified blood-kidney-urine circuit model, in which systemic priming of circulating CD8⁺ T pools is followed by renal recruitment, tissue retention and functional reprogramming of kidney-infiltrating populations, cytotoxic and inflammatory tissue injury, and subsequent release of intrarenal immune signatures into urine. Circulating CD8⁺ T cells include IFN-I-primed naïve-like, effector-memory, and cytotoxic subsets that contribute to systemic immune activation. Within the kidney, infiltrating CD8⁺ T cells display pronounced clonal expansion, tissue-resident and exhaustion-associated phenotypes, and metabolic reprogramming, all of which correlate with local inflammation and histopathologic severity. Urine-derived CD8⁺ T cells, increasingly recognized as a non-invasive proxy for intrarenal immunity, recapitulate key transcriptional programs of kidney-infiltrating populations and provide a dynamic readout of ongoing renal injury. Across these anatomical niches, CD8⁺ T-cell effector and regulatory functions are shaped by pivotal pathways, including type I IFN conditioning, JAK-STAT signaling, NLRP3 inflammasome activation, mitochondrial stress responses, and modulation by immune checkpoints. Collectively, these insights highlight CD8⁺ T cells as an important effector and regulatory component within the broader multicellular immune network of LN and suggest that resolving their compartmental heterogeneity and signaling circuits may accelerate the development of mechanistically grounded biomarkers and targeted immunomodulatory strategies.