Lupus prone DBA/2 (DBA) CD4 T cells exhibit greater B cell help, poorer help for CD8 cytotoxic T lymphocytes (CTL) and induce more severe renal disease compared to B10.D2 CD4 T cells in parent-into F1 (P→F1) mice. (123.27)

Abstract

Abstract Transfer of parental B6 T cells into B6D2F1 (B6→F1) mice results in acute graft-vs- host disease (GVHD) due to donor CD8 CTL that eliminate host cells. Donor CD8 CTL fail to mature in the opposite parental transfer (DBA→F1) resulting in chronic lupus-like GVHD and severe renal disease. To determine whether CTL failure and subsequent lupus like disease in DBA→F1 mice is an intrinsic CD8 defect or extrinsic due to poor CD4 help, female CD4 and CD8 T cells were purified from DBA or C57/Bl background, MHC identical (H-2d) B10.D2 donor T cells and transferred in all 4 possible combinations into female F1 mice. Transfer of B10.D2 CD4 +B10.D2 CD8 (D2+D2→F1) mice and DBA+DBA→F1 mice (positive controls) exhibited the expected acute and chronic GVHD phenotype respectively at 2 weeks. For mixed subsets, D2+ DBA→F1 exhibited a 2 week phenotype not significantly different from control acute GVHD indicating that normal (D2) CD4 help could correct a DBA CD8 CTL defect seen as absent KRLG-1 upregulation. By contrast, DBA+D2→F1 mice exhibited an intermediate phenotype significantly different from either control group indicating that normal D2 CD8 CTL maturation was significantly impaired with DBA CD4 help. Long term, only DBA+DBA→F1 and DBA+D2→F1 mice exhibited lupus autoantibodies or renal disease. Thus, DBA CD4 T cells are the primary determinant of clinical lupus in this model by virtue of greater help for autoreactive B cells and poorer help for down regulatory CD8 CTL.