TCR ACTIVATION OF ZAP70 IS IMPAIRED IN CD4(+)CD8(+) THYMOCYTES AS A CONSEQUENCE OF INTRATHYMIC INTERACTIONS THAT DIMINISH AVAILABLE P56(LCK)

The fate of developing CD4(+)CD8(+) thymocytes is determined by signal s transduced through surface TCR complexes. Here, we report that cross -linking of TCR on CD4(+)CD8(+) thymocytes fails to activate ZAP70 pro tein tyrosine kinase and fails to initiate downstream signaling events , unless the TCR are coaggregated with surface coreceptor molecules. T CR signaling in CD4(+)CD8(+) thymocytes is impaired because the number of available p56(lck) molecules is diminished by intrathymic CD4-1a i nteractions that initially activate p56(lck) molecules, which are subs equently degraded. As a consequence of intrathymic CD4-1a interactions , TCR zeta chains are initially phosphorylated to recruit ZAP70 molecu les, but the recruited ZAP70 molecules are not subsequently phosphoryl ated, resulting in TCR complexes that are stably associated with inact ive ZAP70 molecules. Thus, intrathymic interactions that diminish p56( lck) regulate TCR signaling thresholds and affect TCR structure in dev eloping CD4(+)CD8(+) thymocytes.