A Systemic Lupus Erythematosus Endophenotype Characterized by Increased CD8 Cytotoxic Signature Associates with Renal Involvement

Systemic lupus erythematosus (SLE) is a highly heterogeneous disease with limited therapeutic options, where clinical manifestations are the result of activation of innate and adaptive immune mechanisms. The elucidation of these mechanisms is critical for identifying novel therapeutic targets and agents that are more likely to benefit individual patients. In this study we investigated the role that CD8+ T cells play in SLE. We studied CD8+ T cell activity in two different cohorts of SLE patients under standard of care (n = 65 total). The analyses included phenotyping of T cell differentiation, intracellular cytokine staining, and whole blood gene expression. We identified a subset of SLE patients (between 30 and 45%) with elevated numbers of terminally differentiated CD8+ T cells, identified as CCR7−CD45RAint-hiCD28−. We refer to this phenotype as cytotoxic, as it is accompanied by an increase in perforin and granzyme B expression and is correlated with a whole blood gene module of cytotoxic activity (p < 5 × 10−9). Consistent with the potential for tissue damage, this cytotoxic phenotype associates with lupus nephritis (p < 0.02). We have identified an SLE endophenotype, characterized by the increase in terminally differentiated CD8+ T cells that correlated with cytotoxic signature and renal manifestations of the disease. These findings suggest that this subgroup of SLE patients may benefit specifically from therapies that block CD8+ T cell activation and differentiation.