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–ITAM to Thymocyte Selection
Address correspondence to Ada M. Kruisbeek, Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands. Phone: 31-20-5122056; Fax: 31-20-5122057; E-mail: ma.v.halem{at}nki.nl
The immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 chains associated with the T cell receptor (TCR) are crucial for TCR signaling. To probe the role of the CD3
–ITAM in T cell development, we created knock-in mice in which the CD3 chain of the TCR complex is replaced by a mutant signaling-deficient CD3 chain, lacking the CD3–ITAM. This mutation results in considerable impairment in positive selection in the polyclonal TCR repertoire. When CD3–
ITAM mice are crossed to mice expressing transgenic F5 TCRs, their thymocytes are completely unable to perform positive selection in vivo in response to intrathymic ligands. Also, the in vitro positive selection response of double-positive (DP) thymocytes with F5–CD3–ITAM mutant receptors to their agonist ligand and many of its variants is severely impaired or abrogated. Yet, the binding and dissociation constants of agonist ligands for the F5 receptor are not affected by the CD3–ITAM mutation. Furthermore, DP thymocytes with mutant receptors can respond to agonist ligand with normal antigen sensitivity and to normal levels, as shown by their ability to induce CD69 up-regulation, TCR down-regulation, negative selection, and ZAP70 and c-Jun NH2-terminal kinase activation. In sharp contrast, induction of extracellular signal-regulated kinase (ERK) activation and linker for activation of T cells (LAT) phosphorylation are severely impaired in these cells. Together, these findings underscore that intrinsic properties of the TCR–CD3 complex regulate selection at the DP checkpoint. More importantly, this analysis provides the first direct genetic evidence for a role of the CD3–ITAM in TCR-driven thymocyte selection.
Key Words: thymocyte selection • CD3–ITAM • ITAM multiplicity • T cell activation • TCR signaling
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