Two Src family tyrosine kinases, Lck and Fyn, provide critical functions that predicate the generation of the most proximal signals emanating from the antigen receptor complex in T cells (1, 2). Lck-and Fyn-dependent phosphorylation of many cellular substrates is readily detectable within seconds after T cell receptor engagement (3), and the provision of catalytic activity requires an intact molecular structure (4) and post-translational lipid modifications of these kinases (5-7).Similar to other Src family kinases, Lck and Fyn contain a short N-terminal lipid-modified region, a unique domain, Src homology 3 (SH3) 3 and SH2 domains, a linker region, a catalytic domain, and a C-terminal tail involved in negative regulation of function (8). Biochemical and crystallographic studies revealed that kinase activity is regulated through reversible phosphorylation of two key tyrosine residues. Specifically, the negative regulatory Tyr 505 and Tyr 528 on Lck and Fyn, respectively, and the positive regulatory Tyr 394 and Tyr 417 of Lck and Fyn, respectively, are positioned within the activation loops of their respective kinase domains (9 -12). As Lck and Fyn can be phosphorylated on either of these two regulatory tyrosine residues, the activation of Src kinases is modeled as a sequential two-step mechanism, which allows transitions between three functionally different states (4, 13). The inactive, autoinhibitory conformation is supported in large part by 2-week intra-molecular interactions formed between the SH2 domain and the phosphorylated C-terminal tyrosine and the SH3 domain and the linker region, which cooperatively contribute to down-regulate the kinase activity. CD45-mediated dephosphorylation of the C-terminal phosphotyrosine results in an "open" structure and an active conformation of the kinase domain (14). This initial step of kinase activation can be counteracted by action of the C-terminal Src kinase (Csk) (15, 16). In the second step, full kinase activity is achieved upon phosphorylation of the positive regulatory tyrosine in the activation loop (17).Although not accounting for all possible activation scenarios, this simplified model highlights the important difference between the two activation steps of Lck and Fyn kinases. The initial transition from "closed" to open conformation is con-

No abstract

Genomic disruption of Fyn has not been associated with an immune-deficient phenotype, notwithstanding the profound impairment in IL-2 production by T cells derived from Fyn-deficient animals observed in vitro. The results presented demonstrate that Fyn deficient animals succumb to influenza infection ahead of the protective expansion of lung infiltrating T cells and viral clearance observed in wild-type hosts. Formal proof that Fyn-dependent IL-2 production mediates T cell expansion in vivo is provided using a model of T cell induced enteropathy. Specifically, Fyn deficient naïve T cells do not induce colitis in SCID animals due to their lack of expansion, and Fyn re-expression rescues both IL-2 production and its capacity to support in vivo expansion leading to colitis. These results reconcile the obligatory role of Fyn in T cell activation and autocrine IL-2 supported growth; and underscore the mechanism through which its function is integrated with and regulated by Lck.