WT CD4 T cells are unable to prevent the rejection of allogeneic BMCs by CTLA-4–deficient CD4 cells in mice treated with anti-CD8, 3 Gy TBI, and anti-CD154. In recipients in which all peripheral CD4 cells were derived from WT progenitors, 100% (5 of 5) developed and maintained long-term mixed chimerism. In contrast, recipients containing CD4 cells that were either entirely TKO-derived or included an approximately 1:1 mixture of TKO- and WT-derived cells failed to establish durable mixed chimerism (0/10 for WT-TKO and 1/10 for TKO).