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

Chronic antigen exposure in cancer and infection generates hypofunctional, stem-like CD8 T cells that replenish tissue effector cells for tumor or pathogen control. CD8 T cells infiltrate kidneys in systemic lupus erythematosus, but their origin, differentiation, and function remain incompletely understood. We identified in lupus-prone mice TCF1⁺ stem-like CD8 T cells in renal-draining lymph nodes that underwent TCR-dependent, antigen-driven expansion with differentiation into cytotoxic kidney-infiltrating cells that promoted tissue injury contingent on CD4 T cell help and IL-21/IL-15 signaling. CD8 T cell differentiation was marked by persistent AP-1 activity and cytotoxic function despite immune checkpoint upregulation. We found a parallel program of CD8 T cell differentiation in kidneys of patients with lupus nephritis, reflecting shared pathogenesis. This T cell differentiation program is analogous to that in chronic infections and cancer, indicating conservation across states of chronic antigen stimulation; however, CD8 T cells in systemic autoimmunity retain effector function despite terminal differentiation.