On the signaling of the pre-TCR

The function of tyrosine kinase activity during canonical T cell antigen receptor (TCR) signaling in T cells has been intensively studied over the past 18 years. This signaling pathway is critical at multiple stages of T cell development. Which kinase family members are used at these stages has been largely described for the Src-family kinases (SFK), but less is known of the Syk-family kinases. Previous studies have suggested that neither of the Syk-family kinases, Syk or ZAP-70, serves a unique function during the earliest stage that requires signaling through the antigen receptor, the β-selection stage that uses the pre-TCR. Moreover, ZAP-70 has previously only been shown to have a unique role in propagating thymic selection signals. This thesis establishes the relative levels of both Syk-family kinases in all major thymocytes subsets. It will demonstrate that Syk and ZAP-70 serve unique, temporally separable functions during early thymocyte development and that pre-TCR signaling continues well after the originally established DN3 stage and on through multiple developmental stages until immediately before positive selection. Further, it will be shown that the phosphatase CD45, a positive regulator of antigen receptor signaling, is also critically required for early developmental progression, including the newly described sustained pre-TCR stages