Nephritogenic cytokines and disease in MRL-Fas(lpr) kidneys are dependent on multiple T-cell subsets

Background, Renal parenchymal cells produce cytokines, colony-stimulating f actor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha), which recruit autoreactive T cells and, in turn, elicit renal injury in MRL-Fas(lpr) mice. Methods. To determine whether select T-cell populations regulate intrarenal nephritogenic cytokines (CSF-1, GM-CSF, and TNF-alpha) and renal disease, we compared MRL-Fas(lpr) mice that are genetically deficient in T-cell rece ptor (TCR) alpha beta T cells, CD4 T cells, and major histocompatibility co mplex class I (MHC class I), lacking CD8 and double negative (DN)T cells, w ith wild-type: mice. To identify the T cells instrumental in downstream (ef fector) events, we delivered CSF-1 or GM-CSF into the kidney via gene trans fer in these select T-cell-deficient and wild-type strains. Results. Intrarenal CSF-1. GM-CSF, and TNF-alpha were absent or dramaticall y reduced in TCR alpha beta, CD4, and class I-deficient MRL-Fas(lpr) strain s as compared with wild type mice. In addition, the decrease in CSF-1. GM-C SF. and TNF-alpha was associated with a reduced kidney leukocytic infiltrat es and spontaneous autoimmune nephritis. Intrarenal ex vivo retroviral gene transfer of CSF-1 and GM-CSF failed to elicit nephritis in these T-cell-de ficient MRL strains (TCR alpha beta. CD4. CD8/DN) as compared with wild-typ e mice. Conclusions. Multiple T-cell populations initiate renal dis ease by increas ing intrarenal nephritogenic cytokines. CSF-1, GM-CSF. and TNF-alpha. CSF-1 and GM-CSF recruit additional CD4 and CDS and DN T cells, which augment do wnstream events. resulting in progressive autoimmune renal disease. We sugg est that MRL-Fas(lpr) kidney disease is driven by a T-cell amplification fe edback loop dependent on multiple T-cell populations.