Organ injury in systemic autoimmunity is mediated by stem-like CD8⁺ T cells arising from tissue-draining lymph nodes

Although loss of B cell tolerance, autoantibody production, and immune complex deposition are hallmarks of systemic lupus erythematosus (SLE), CD8⁺ T cell infiltration in the kidneys is the best predictor of poor prognosis in lupus nephritis, a severe manifestation of SLE. Here, we examined the origin, differentiation, and functional consequences of CD8⁺ T cells infiltrating kidneys in lupus-prone mice. TCF-1⁺ stem-like CD8⁺ T cells in renal-draining lymph nodes underwent T cell receptor (TCR)-dependent, antigen-driven expansion with differentiation into cytotoxic kidney-infiltrating cells that promoted tissue injury contingent on CD4⁺ T cell help and interleukin (IL)-21 and IL-15 signaling. CD8⁺ T cell differentiation was marked by persistent AP-1 activity and cytotoxic function despite increased expression of immune checkpoints. A parallel program of CD8⁺ T cell differentiation in the kidneys of patients with lupus nephritis reflected shared pathogenesis. Thus, a T cell differentiation program analogous to that in chronic infections and cancer is found in lupus; however, CD8⁺ T cells in systemic autoimmunity retain effector function despite terminal differentiation.