Background and aims Systemic lupus erythematosus (SLE) is a highly heterogeneous disease with limited therapeutic options, where clinical manifestations are the result of multiple pathological mechanisms. The elucidation of these mechanisms is critical for identifying novel therapeutic targets and agents that are more likely to benefit individual patients. Here we investigated the role that CD8⁺ T cells play in SLE.

Methods We studied CD8⁺ T cell differentiation in SLE patients under standard of care (n=80), from two different cohorts. The analyses included phenotyping of T cell differentiation, intracellular cytokine staining and whole blood gene expression.

Results We identified a subset of lupus patients that have elevated numbers of terminally differentiated CD8⁺ T cells, identified as CCR7¯CD45RA^int-hiCD28¯. This increase in terminally differentiated CD8⁺ T cells is accompanied by an increase in perforin and granzyme B production and correlated with a whole blood gene module of cytotoxic activity (p<5x10^-9). More importantly, this phenotype was associated with lupus nephritis (p<0.02).

Conclusions We have identified a lupus endophenotype, characterised by the increase in terminally differentiated CD8⁺ T cells, which correlated with cytotoxic activity and renal manifestations of the disease. These findings suggest that this group of patients may benefit from therapies that block CD8⁺ T cell activation and differentiation.