Infiltrating macrophages and T cells are instrumental in autoimmune kidney destruction of MRL-Fas^lpr mice. We report that the β-chemokine RANTES, a chemoattractant for macrophages and T cells, is up-regulated in the MRL-Fas^lpr kidney prior to injury, but not normal kidneys (MRL-++, C3H-++) and increases with progressive injury. Furthermore, we establish an association between RANTES expression in the kidney and renal damage using a gene transfer approach. Tubular epithelial cells genetically modified to secrete RANTES infused under the renal capsule incites interstitial nephritis in MRL-Fas^lpr, but not MRL-++ or C3H-++ mice. RANTES recruits predominantly macrophages (Mø) and CD4⁺ and CD8⁺ T cells. In contrast, gene transfer of CSF-1, another molecule up-regulated simultaneously with RANTES in MRL-Fas^lpr kidneys, promotes the influx of Mø, CD4⁺ T cells and the unique double-negative (DN) T cells (CD4^-,CD8^-), which are prominent in diseased MRL-Fas^lpr kidneys. Thus, RANTES and CSF-1 recruit distinct T cell populations into the MRL-Fas^lpr kidney. In addition, delivery of RANTES and CSF-1 into the kidney of MRL-Fas^lpr mice causes an additive increase in pathology. We suggest that the complementary recruitment of T cell populations by RANTES (CD4, CD8) and CSF-1 (CD4, DN) promotes autoimmune nephritis in MRL-Fas^lpr mice.