Proline-rich tyrosine kinase-2 is critical for CD8 T-cell short-lived effector fate

Department of Medicine, Division of Rheumatology, The Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, and Graduate Program in Biomedical Sciences, University of California, San Francisco, CA 94143-0795, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2010; 107(37):16234-9. DOI: 10.1073/pnas.1011556107
Source: PubMed


T-cell interactions with antigen-presenting cells are important for CD8 T-cell effector or memory fate determination. The integrin leukocyte function-associated antigen-1 (LFA-1) mediates T-cell adhesion but the contribution of LFA-1-induced signaling pathways to T-cell responses is poorly understood. Here we demonstrate that proline-rich tyrosine kinase-2 (PYK2) deficiency impairs CD8 T-cell activation by synergistic LFA-1 and T-cell receptor stimulation. Furthermore, PYK2 is essential for LFA-1-mediated CD8 T-cell adhesion and LFA-1 costimulation of CD8 T-cell migration. During lymphocytic choriomeningitis virus infection in vivo, PYK2 deficiency results in a specific loss of short-lived effector CD8 T cells but does not affect memory-precursor CD8 T-cell development. Similarly, lack of LFA-1 primarily impairs the generation of short-lived effector cells. Thus, PYK2 facilitates LFA-1-dependent CD8 T-cell responses and promotes CD8 T-cell short-lived effector fate, suggesting that PYK2 may be an interesting therapeutic target to suppress exacerbated CD8 T-cell responses.

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Available from: Arthur Weiss, Jun 30, 2014
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    • "In addition, it has been demonstrated that ADAP is required for TCR-stimulated cell adhesion mediated by β1 and β2 integrins (Griffiths et al., 2001; Peterson et al., 2001), a process regulated by an ADAP/SKAP-55 signaling module (Wang et al., 2003, 2007; Kliche et al., 2006). As for Pyk2, its tyrosine phosphorylation as a consequence of integrindependent outside-in signaling was earlier demonstrated (Li et al., 1996; van Seventer et al., 1998; Zheng et al., 1998), and it was shown that Pyk2 regulates TCR-stimulated, LFA-1–dependent CD8 + cell adhesion (Beinke et al., 2010). Little is known on the potential involvement of SLP-76 and Pyk2, as well as of ADAP, in chemokine-stimulated T-cell adhesion dependent on integrins. "
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