Kidney-infiltrating CD4+ T-cell clones promote nephritis in lupus-prone mice

In systemic lupus erythematosus, CD4(+) T cells play key roles in the initiation and promotion of autoantigen-specific humoral immunity, and indirect evidence suggests that T cells are pathogenic effectors in lupus nephritis. The contribution of kidney-infiltrating T cells to nephritis, however, has not been verified because of the difficulty in directly analyzing organ-infiltrating T cells. Here, we examined the pathogenic roles of autoreactive cytokine-expressing CD4(+) T cells from the kidneys of early nephritic MRL/lpr mice. Interferon (IFN)-gamma-secreting cells were enriched among CD5(high)CD4(+) T cells found in the inflamed kidneys. Using single-cell analysis of the T-cell receptor (TCR)(high)CD5(high)CD4(+) T cells from the kidneys of early nephritic MRL/lpr mice, two IFN-gamma-expressing CD4(+) T cell clones, MLK2 and MLK3, were identified. CD4(+) T cells transduced with the T-cell receptor genes from each clone responded to splenic dendritic cells in an MHC class II -dependent manner, but not to B cells or macrophages. MLK3-transduced CD4(+) T cells proliferated in the spleens of prenephritic mice, promoted nephritis progression upon adoptive transfer, and enhanced the deposition of C3 without promoting anti-double-stranded DNA antibody production. Thus, CD4(+) T cells in the inflamed kidneys of MRL/lpr mice contribute to nephritis progression. Kidney International (2012) 82, 969-979; doi:10.1038/ki.2012.242; published online 4 July 2012