The TCR ζ-Chain Immunoreceptor Tyrosine-Based Activation Motifs Are Sufficient for the Activation and Differentiation of Primary T Lymphocytes

Abstract

The TCR complex signals through a set of 10 intracytoplasmic motifs, termed immunoreceptor tyrosine-based activation motifs (ITAMs), contained within the γ-, δ-, ε-, and ζ-chains. The need for this number of ITAMs is uncertain. Limited and contradictory studies have examined the ability of subsets of the TCR’s ITAMs to signal into postthymic primary T lymphocytes. To study signaling by a restricted set of ITAMs, we expressed in transgenic mice a chimeric construct containing the IAs class II MHC extracellular and transmembrane domains linked to the cytoplasmic domain of the TCR ζ-chain. Tyrosine phosphorylation and receptor cocapping studies indicate that this chimeric receptor signals T cells independently of the remainder of the TCR. We show that CD4+ and CD8+ primary T cells, as well as naive and memory T cells, are fully responsive to stimulation through the IAs-ζ receptor. Further, IAs-ζ stimulation can induce primary T cell differentiation into CTL, Th1, and Th2 type cells. These results show that the ζ-chain ITAMs, in the absence of the γ, δ, and ε ITAMs, are sufficient for the activation and functional maturation of primary T lymphocytes. It also supports the isolated use of the ζ-chain ITAMs in the development of surrogate TCRs for therapeutic purposes.