Single-cell transcriptomes and T cell receptor sequences of CD4 or CD8 single positive T lymphocytes from peripheral blood or urine of lupus nephritis patients at flare.

Proliferative lupus nephritis (LN) is triggered by deposition of autoantibodies in glomeruli and paralleled by a T cell-rich kidney infiltrate. Although these T cells have been attributed with propagation of tissue injury, it is unclear how they are activated and whether T cell autoreactivity drives the local inflammation. Kidney-infiltrating T cells are also observed in urine, where they have high resemblance with interstitial T cells. Therefore, urinary T cells are a proxy to investigate tissue pathogenesis. Here, we analyzed urinary T cells to elucidate if a kidney-specific T cell autoimmune reaction contributes to tubulointerstitial inflammation in LN. Using single cell RNA sequencing, we compared transcriptomes and clonotypes of T cells from blood and urine of patients with active LN and show that urinary T cells were mostly activated CD8 effector memory cells recruited from a circulating CX3CR1+ subset. Several urinary CD8 T cell clones were expanded. However, upon in vitro testing of their T cell receptors, we did not observe autoreactivity against autologous tubular epithelial cells. Instead, approximately 20% of expanded clonotypes were Epstein-Barr virus- or cytomegalovirus specific, but respective viral antigens were undetectable in kidney biopsies or urine. Conversely, kidney-infiltrating T cells had access to interleukin-15 and interferon (IFN) β and stimulation with these cytokines was sufficient to trigger degranulation and production of tumor necrosis factor, IFN γ and granzyme K. Together, these results show that CD8+CX3CR1+ T cells are recruited into the kidney in LN, where they are activated by cytokines enabling them to contribute to local inflammation.