Original Article

Partially Phosphorylated T Cell Receptor Molecules Can Inhibit T Cell Activation

Correspondence to: Paul M. Allen, Washington University School of Medicine, Dept. of Pathology, Campus Box 8118, 660 South Euclid Ave., St. Louis, MO 63110. Tel:314-362-8758 Fax:314-362-8888 E-mail:allen{at}immunology.wustl.edu.

The T cell receptor complex (TCR) chain is constitutively tyrosine phosphorylated specifically at two of the six immunoreceptor tyrosine-based activation motif (ITAM) tyrosine residues in resting peripheral T cells. Further phosphorylation of is induced by both agonist and antagonist ligands of the TCR, with agonists inducing complete phosphorylation of the ITAM tyrosines. After antagonist stimulation, phosphorylation is incomplete and generates discrete forms of partially phosphorylated ITAMs. Here, we mutate specific tyrosines in chimeric human CD8- molecules to reflect phosphorylation in resting T cells as well as phosphorylation induced by agonist and antagonist ligands. We demonstrate that such partially phosphorylated TCR- species can inhibit IL-2 production in T cell hybridomas and proliferation in T cell clones. This reveals a previously unrecognized, inhibitory function of partially phosphorylated ITAMs. These findings support the concept that TCR antagonism can arise through the generation of an inhibitory signal within the TCR complex and that constitutive phosphorylation in resting T cells is an inhibitory signaling environment.

Key Words: T cell signaling, ITAM, CD3 complex phosphorylation, TCR antagonism, altered peptide ligand

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