THE SYK AND ZAP-70 SH2-CONTAINING TYROSINE KINASES ARE IMPLICATED IN PRE-T CELL-RECEPTOR SIGNALING

An early stage in thymocyte development, after rearrangement of the be ta chain genes of the T cell receptor (TCR), involves expression of th e pre-TCR complex and accompanying differentiation of CD4(-)CD8(-) dou ble negative (DN) cells to CD4(+)CD8(+) double positive (DP) cells. Th e ZAP-70 and Syk tyrosine kinases each contain two N-terminal SH2 doma ins that bind phosphorylated motifs in antigen receptor subunits and a re implicated in pre-T receptor signaling. However, mice deficient in either ZAP-70 or Syk have no defect in the formation of DP thymocytes. Here we show that, in mice lacking both Syk and ZAP-70, DN thymocytes undergo beta chain gene rearrangement but fail to initiate clonal exp ansion and are incapable of differentiating into DP cells after expres sion of the pre-TCR These data suggest that the ZAP-70 and Syk tyrosin e kinases have crucial but overlapping functions in signaling from the pre-TCR and hence in early thymocyte development.