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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    • "A similar requirement for T cell polarity in SLEC differentiation was reported for both Pyk2-deficient and LFA-1 deficient T cells, which exhibit impaired SLEC differentiation after LCMV infection (Beinke et al., 2010). Interestingly, as antigen concentrations decrease, CD8 hi proximal daughters maintain their ability to bind strongly to antigenbearing DCs in vitro as well as to proliferate in vivo. "
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    • "Knockout of Cas-L results in reduced T cell motility, but with no obvious effects on T cell activation (Regelmann et al., 2006). However, Cas- L partners with SLP-76 and Pyk2 in T cells and recent findings show that Pyk2 is involved in CD8 T cell differentiation (Beinke et al., 2010). These results suggest that mechanotranduction may have roles beyond TCR triggering and motility. "
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