El copyright pertenece a The Rockefeller University PressT lymphocytes recognize antigen using the TCR, a disulphide-linked heterodimer closely associated with a nonpolymorphic polypeptide complex on the cell surface termed CD3 (1-3). The vast majority of mature T cells in peripheral blood and lymphoid organs use the TCR [alfa/beta], while a minor (1-10%) subpopulation have been shown to express TCR [gamma/delta] (4-7). Recently, the finding that both murine Thy-1 + dendritic epidermal cells (8) and intestinal intraepithelial lymphocytes (9) express mainly the [gamma,delta] receptor led some investigators to propose that T cells carrying this complex could be involved in surveillance of epithelial cell surfaces (10). Interestingly, epidermal cells lack the CD4 and CD8 molecules found on virtually all CD3 [alfa/beta] T cells, while intestinal epithelial cells are exclusively CD8+ , roughly half of them lacking the Thy.l marker. Since during ontogeny, cells bearing the [gamma/delta] receptor appear before those bearing [alfa/beta] (10), we decided to explore their presence throughout human T cell development. We now report that a considerable proportion of fetal liver T cells in 20-wk-old human fetuses are able to grow in IL-2 and express the [gamma/delta] receptor. One striking feature of these cells, besides their anatomical location, is the fact that up to 20% of them express the CD4 marker not previously described on the [gamm/delta] T cells. Analysis of this population at the clonal level reveals that, in contrast with the other CD4 [alfa/beta] T cell clones and with [gamma/delta] double-negative (DN) cells, [gamma/delta] CD4+ cells do not produce IL-2 and are devoid of any cytolytic activity. Thus, they display different properties than either CD4+ [alfa/beta] T cells or [gamma/delta] DN cells, suggesting that CD4+ [gamma/delta] T cells are an ontogenically restricted population expressed at early stages of development, with unique features in the T cell compartment.Peer reviewed