Although loss of B cell tolerance and autoantibody production are key features of lupus nephritis, CD8+ T cell kidney infiltration is a strong indicator of a poor outcome. Now, findings published in Immunity provide insights into how CD8+ T cells cause kidney damage in lupus nephritis.

Al Souz et al showed that CD8+ T cells in the kidneys of lupus-prone MRL/lpr mice had a cytotoxic (granzyme B) phenotype, expressed exhaustion markers (PD-1 and TIM3) despite retaining their effector functions, and were associated with worsening disease. Depletion of these cells stabilized disease. Further research revealed that these cells arise from stem-like CD8⁺ T cell precursors in kidney-draining lymph nodes, where they undergo clonal expansion, migrate to the kidneys and differentiate into effector CD8⁺ T cells. The authors show that this process is antigen dependent rather than being a result of bystander activation.