SHP-1 acts as a key regulator of alloresponses by modulating LFA-1-mediated adhesion in primary murine T cells

MG Sauer, J Herbst, U Diekmann… - … and Cellular Biology, 2016 - Taylor & Francis
MG Sauer, J Herbst, U Diekmann, CE Rudd, C Kardinal
Molecular and Cellular Biology, 2016Taylor & Francis
The clinical potential of transplantation is often reduced by T cell-mediated alloresponses
that cause graft rejection or graft-versus-host disease. Integrin-mediated adhesion between
alloreactive T cells and antigen-presenting cells is essential for allorejection. The identity of
the signaling events needed for the activation of integrins such as LFA-1 is poorly
understood. Here, we identified a novel role of the protein tyrosine phosphatase SHP-1 in
the regulation of murine LFA-1-mediated adhesion in an allograft setting. Upon …
The clinical potential of transplantation is often reduced by T cell-mediated alloresponses that cause graft rejection or graft-versus-host disease. Integrin-mediated adhesion between alloreactive T cells and antigen-presenting cells is essential for allorejection. The identity of the signaling events needed for the activation of integrins such as LFA-1 is poorly understood. Here, we identified a novel role of the protein tyrosine phosphatase SHP-1 in the regulation of murine LFA-1-mediated adhesion in an allograft setting. Upon alloactivation, SHP-1 activity is reduced, resulting in an increase in LFA-1 adhesion compared to that for syngeneically activated T cells. The importance of these differential activation properties was further indicated by small interfering RNA (siRNA) knockdown of SHP-1 in syngeneically and allogeneically stimulated T cells. Mechanistically, SHP-1 modulated the binding of SLP-76 to ADAP by dephosphorylation of the YDGI tyrosine motif of ADAP, a known docking site for the Src family kinase Fyn. This novel key role of SHP-1 in the regulation of LFA-1-mediated adhesion may provide a new insight into T cell-mediated alloresponses and may pave the way to the development of new immunosuppressive pharmaceutical agents.
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