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*
Laboratory of Mammalian Genes & Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and
Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
Whether a developing thymocyte becomes positively or negatively
selected is thought to be determined by the affinity/avidity of its TCR
for MHC/peptide ligands expressed in the thymus. Presumably,
differences in affinity translate into differences in the potency of
the ensuing TCR-mediated signals, and these differences in signal
strength determine the outcome of thymocyte selection. However, there
is little direct evidence establishing a relationship between
TCR-ligand affinity and signal strength during positive and negative
selection. The TCR complex contains multiple signaling motifs, known as
immunoreceptor tyrosine-based activation motifs (ITAMs) that are
required for T cell activation. To examine the effects of TCR signal
strength on selection, the signaling potential of the TCR was modified
by substituting transgenic TCR 
-chains containing either three, one,
or zero ITAMs for endogenous (3-ITAM) -chain. These -chain
variants were then bred into different 
ßTCR transgenic
backgrounds. We report that reductions in TCR signaling potential have
distinct effects on the selection of thymocytes expressing different
TCRs, and that the requirement for -chain ITAMs critically depends
upon the specificity and apparently, affinity, of the TCR for its
selecting ligand(s).
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