The tyrosine phosphatase SHP-1 promotes T cell adhesion by activating the adaptor protein CrkII in the immunological synapse

The adaptor protein CrkII is a key regulator of T cell adhesion through the recruitment of the Rap1-guanine exchange factor, C3G. Subsequently, Rap1 activates the integrin LFA-1 leading to T cell adhesion and interaction with antigen presenting cells (APC). The interphase between T cell and APC is known as the immunological synapse (IS). It is characterized by specific organization of proteins that can be divided into central supramolecular activation clusters (c- SMAC) and peripheral supramolecular activation clusters (p-SMAC). Using TIRF microscopy and support lipid bilayers we determined that activated Rap1 was recruited to the IS. Within the IS, Rap1 was localized to the p-SMAC. C3G and the active (dephosphorylated) form of CrkII were also localized to the same compartment. In contrast, inactive (phosphorylated) CrkII was limited to the c-SMAC. We then showed that activation of CrkII and subsequent trafficking from the c-SMAC to the p-SMAC were regulated by the phosphatase SHP-1 downstream of the antigen receptor. In the p-SMAC, CrkII recruited C3G, leading to Rap1 activation and LFA-1 mediated adhesion. Functionally, SHP-1 was necessary for both adhesion and migration of T cells. Thus, we uncovered a new signaling pathway where SHP-1 acts through CrkII to reshape the pattern of Rap1 activation in the IS