IL-21, Inflammatory Cytokines and Hyperpolarized CD8⁺ T Cells Are Central Players in Lupus Immune Pathology

Systemic lupus erythematous (SLE) is a chronic autoimmune disorder, broadly characterized by systemic inflammation along with heterogeneous clinical manifestations, severe morbidity, moribund organ failure and eventual mortality. In our study, SLE patients displayed a higher percentage of activated, inflamed and hyper-polarized CD8⁺ T cells, dysregulated CD8⁺ T cell differentiation, significantly elevated serum inflammatory cytokines and higher accumulation of cellular ROS when compared to healthy controls. Importantly, these hyper-inflammatory/hyper-polarized CD8⁺ T cells responded better to an antioxidant than to an oxidant. Terminally differentiated Tc1 cells also showed plasticity upon oxidant/antioxidant treatment, but that was in contrast to the SLE CD8⁺ T cell response. Our studies suggest that the differential phenotype and redox response of SLE CD8⁺ T cells and Tc1 cells could be attributed to their cytokine environs during their respective differentiation and eventual activation environs. The polarization of Tc1 cells with IL-21 drove hyper-cytotoxicity without hyper-polarisation suggesting that the SLE inflammatory cytokine environment could drive the extreme aberrancy in SLE CD8⁺ T cells.