To investigate mechanisms of cell-mediated events in chronic glomerulonephritis, T cell clones were isolated from kidneys of animals with murine chronic graft-vs-host disease. This systemic disorder is induced in normal (C57BL/6× DBA/2) F 1 recipients (H-2 b/d) following transfer of parental (DBA/2) T cells (H-2 d). These studies demonstrate that mouse renal (MR) T cells isolated from nephritic kidneys of diseased recipients are host-derived CD4+ α/β+ T cells. Adoptive transfer of a panel of MR clones to naive (C57BL/6× DBA/2) F 1 recipients reveals distinct functional subsets. One subset does not transfer renal disease, and one induces severe renal inflammation and damage. In vitro proliferative responses of nephritogenic MR clones reveal predominant reactivity toward autologous class II MHC (IE d/IA d) determinants, and selected nephritogenic MR clones preferentially recognize renal Ag preparations derived from normal (C57BL/6× DBA/2) F 1 kidneys. In addition, cytokine profile analysis of MR clones indicates a Th2 pattern with IL-4 and IL-10 expression, although nephritogenic T cell clones also express IFN-γ. These data suggest that the nephritogenic T cell response in chronic graft-vs-host disease is autoreactive in nature and may be restricted by determinants shared by both graft and host (Ia d).