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The TCR -Chain Immunoreceptor Tyrosine-Based Activation Motifs Are Sufficient for the Activation and Differentiation of Primary T Lymphocytes¹

Terrence L. Geiger^*,, David Leitenberg^*, and Richard A. Flavell^2,*

^* Section of Immunobiology, and Department of Laboratory Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510

The TCR complex signals through a set of 10 intracytoplasmic motifs, termed immunoreceptor tyrosine-based activation motifs (ITAMs), contained within the -, -, -, and -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 IA^s class II MHC extracellular and transmembrane domains linked to the cytoplasmic domain of the TCR -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 IA^s- receptor. Further, IA^s- stimulation can induce primary T cell differentiation into CTL, Th1, and Th2 type cells. These results show that the -chain ITAMs, in the absence of the , , and ITAMs, are sufficient for the activation and functional maturation of primary T lymphocytes. It also supports the isolated use of the -chain ITAMs in the development of surrogate TCRs for therapeutic purposes.

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