Two Receptors, Two Kinases, and T Cell Lineage Determination

The T cell antigen receptor (TCR) serves as a paradigm for how membrane receptors transmit signals to the cytoplasm because it controls many aspects of T cell differentiation and function by detecting atom-sized variations in the quality of the ligand that is recognized. The mechanisms that underlie the different signaling outcomes are unclear. Studies that suggest a ligand-tailored, qualitatively different signal are confronted with evidence that favors a quantitative model, and studies of TCR-dependent T cell differentiation in the thymus are no exception. Mature T cells with an alpha beta TCR are classified according to two major distinct subsets based on the mutually exclusive presence of the co-receptors CD4 and CD8, which play essential roles in recognition of the major histocompatibility complex (MHC) class II and I ligands, respectively, and in the recruitment of the tyrosine kinase Lck to the TCR complex. Mature CD4(+) and CD8(+) T cells derive from a common precursor in the thymus, a double-positive (DP) thymocyte, which has both co-receptors. Early signaling models suggested that the differential capacity of CD4 and CD8 to recruit Lck to the TCR underlay lineage decision. A study now shows that differentiation into the CD8(+) lineage requires the TCR-induced increased abundance of the tyrosine kinase zeta chain-associated protein kinase of 70 kD (Zap70). This finding, together with the known importance of Lck in the determination of CD4(+) and CD8(+) lineages, enables us to propose that a balance between the activation of these two kinases by the TCR determines lineage decisions.