We have determined the effect of anti-CD4 or anti-CD8 monoclonal antibody (mAb) treatment from birth on the generation of thelprCD4⁻CD8⁻double-negative (DN) T cell subset and on the development of lupus-like autoimmune syndrome in MRL-lpr/lprmice. Both anti-CD4 and anti-CD8 mAb treatments resulted in a marked inhibition of lymphadenopathy, whereas the development of thelprDN T cells and of the lupus-like autoimmune syndrome strikingly differed in these two groups of mice. The treatment with anti-CD8 mAb almost completely blocked the appearance of thelprDN T cells without any significant effect on the development of lupus-like autoimmune syndrome in MRL-lpr/lprmice. In contrast, mice treated with anti-CD4 mAb failed to develop a lupus-like syndrome, while they still developed thelprDN T cell subset, the predominant population in their lymph nodes, although absolute numbers were markedly diminished. Our results support the idea that CD8⁺T cells are a major source of thelprDN T cells, and that thelprDN T cells play a minor, if any, role in the pathogenesis of lupus-like autoimmune syndrome in MRL-lpr/lprmice.