The T-cell receptor ζ (TCR-ζ) and FcR-γ chains play a critical role in mediating signal transduction. We have previously described HIV glycoprotein 120 (gp120)–specific chimeric immune receptors (CIRs) in which the extracellular domain of CD4 is linked to the signaling domain of ζ (CD4ζ) or γ (CD4γ). Such CIRs are efficiently expressed following retroviral transduction of mature T cells and specifically redirect effector functions toward HIV-infected targets. In this report, we examine development of CD4ζ- or CD4γ-expressing T cells from retrovirally transduced hematopoietic stem cells following bone marrow transplantation. Although CD4ζ/γ-expressing myeloid, NK, and B cells were efficiently reconstituted, parallel development of CD4ζ/γ-expressing T cells was blocked prior to the CD25⁺CD44⁺prothymocyte stage. In contrast, T cells expressing a signaling-defective CIR were efficiently generated. When major histocompatibility complex (MHC) class II–deficient mice were used as transplant recipients, development of CD4ζ/γ-expressing T cells was restored. We conclude that CD4ζ/γ signaling generated following engagement of MHC class II selectively arrests T-lineage development.