The αβ/γδ Lineage Decision

Abstract

An accident of molecular biology in 1984 (1,2) prefaced a roundly unanticipated fact, that vertebrates make two sets of qualitatively distinct T-cells: αβ T-cells and γδ T-cells (3). There are many differences between these cell types, most notably in the antigen receptors that define them. Whereas αβ T-cell receptors (TCRs) mostly recognize complexes of antigenic peptide and major histocompatibility complex (MHC) molecules, γδTCRs recognize a spectrum of cell-associated antigens which seems as diverse as the antigen specificity of immunoglobulins (4). Moreover, in mice lacking Syk kinase, sets of γδ cells fail to develop, like B-cells, whereas αβ T-cell development progresses apparently normally (5, 6). These observations suggest that γδ cells and αβ T-cells are extremely different, and likely to arise from progenitor cells that diverge early during lymphopoiesis. Conversely, there is an obligatory association of TCRγδ and TCRαβ with the polypeptide complex, CD3, that has been used as the defining feature of T-cells. Additionally, many (possibly most) γδ cells arise from the thymus (7, 8). By these criteria, γδ cells and αβ T-cells may be sisters, arising from a late lineage decision of a common intrathymic precursor.