A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity

Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, Department of Microbiology and Immunology, University of California-San Francisco, California, USA.
Nature Immunology (Impact Factor: 20). 10/2010; 11(12):1085-92. DOI: 10.1038/ni.1955
Source: PubMed


To investigate the role of the kinase Zap70 in T cells, we generated mice expressing a Zap70 mutant whose catalytic activity can be selectively blocked by a small-molecule inhibitor. We found that conventional naive, effector and memory T cells were dependent on the kinase activity of Zap70 for their activation, which demonstrated a nonredundant role for Zap70 in signals induced by the T cell antigen receptor (TCR). In contrast, the catalytic activity of Zap70 was not required for activation of the GTPase Rap1 and inside-out signals that promote integrin adhesion. This Zap70 kinase-independent pathway was sufficient for the suppressive activity of regulatory T cells (T(reg) cells), which was unperturbed by inhibition of the catalytic activity of Zap70. Our results indicate Zap70 is a likely therapeutic target.

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Available from: Arthur Weiss, Jun 30, 2014
    • "In marked contrast, our patients had a distinct phenotype with early onset, severe to life-threatening autoimmune disease and only minor lymphocyte abnormalities and no evidence of immune deficiency (Table 1). In mice, defects in both central and peripheral tolerance have been associated with hypomorphic Zap-70 defects and autoimmune features (Siggs et al., 2007;Au-Yeung et al., 2010;Tanaka et al., 2010). In humans, ZAP70 deficiency can alter the thymic stromal compartment, reduce thymic T reg cell numbers, and develop an autoimmune-prone gene expression profile in CD4 T cells (Roifman et al., 2010;Poliani et al., 2013). "
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    • "One possibility is the spatial segregation of TCR and Lck from phosphatases such as CD45 (Davis and Van Der Merwe, 2006; Rossy et al., 2012). Phosphorylated ITAMs serve as recruitment and activation sites for zeta chain-associated protein kinase of 70 kDa (ZAP-70), whose activity is essential in conventional T cells but not in regulatory T cells (Au-Yeung et al., 2010). "
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    • "Selective inhibition of Zap70 kinase activity in mice did not lead to defects in RapI activation or integrin-mediated cell adhesion, as was observed with Zap70 genetic deficiency (Au-Yeung et al., 2010). Likewise, knockdown of interleukin 1 receptor associated kinase 1 by small hairpin RNA induced cell death in a subset of non-Hodgkin's lymphoma cell lines, a phenotype that was completely rescued by expression of a kinase-dead mutant of this protein (Ngo et al., 2011). "
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