Research ArticleImmunology

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

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Science Signaling  08 Aug 2017:
Vol. 10, Issue 491, eaal2880
DOI: 10.1126/scisignal.aal2880

Shaping T cell activation

Efficient activation of the T cell receptor (TCR) on T cells by antigen-presenting cells (APCs) requires the formation of a stable interface (the immunological synapse) between both cell types. T cell adhesion to APCs is mediated by the T cell integrin LFA-1, the activation of which depends on the small guanosine triphosphatase (GTPase) Rap1. Patients with mutations in the gene encoding Rap1 have an immunodeficiency caused by defective T cell adhesion. Azoulay-Alfaguter et al. used live-cell imaging to show that the adaptor protein CrkII, which is required for Rap1 activation, was recruited from the central region of the immunological synapse to the peripheral region where Rap1 and LFA-1 were localized. This translocation depended on the TCR-stimulated activity of the phosphatase SHP-1, which dephosphorylated the inactive (phosphorylated) form of CrkII. Together, these data suggest that targeting the phosphorylation state of CrkII may enable therapeutic modulation of T cell adhesion and activation.


The adaptor protein CrkII regulates T cell adhesion by recruiting the guanine nucleotide exchange factor C3G, an activator of Rap1. Subsequently, Rap1 stimulates the integrin LFA-1, which leads to T cell adhesion and interaction with antigen-presenting cells (APCs). The adhesion of T cells to APCs is critical for their proper function and education. The interface between the T cell and the APC is known as the immunological synapse. It is characterized by the specific organization of proteins that can be divided into central supramolecular activation clusters (c-SMACs) and peripheral SMACs (p-SMACs). Through total internal reflection fluorescence (TIRF) microscopy and experiments with supported lipid bilayers, we determined that activated Rap1 was recruited to the immunological synapse and localized to the p-SMAC. C3G and the active (dephosphorylated) form of CrkII also localized to the same compartment. In contrast, inactive (phosphorylated) CrkII was confined to the c-SMAC. Activation of CrkII and its subsequent movement from the c-SMAC to the p-SMAC depended on the phosphatase SHP-1, which acted downstream of the T cell receptor. In the p-SMAC, CrkII recruited C3G, which led to Rap1 activation and LFA-1–mediated adhesion of T cells to APCs. Functionally, SHP-1 was necessary for both the adhesion and migration of T cells. Together, these data highlight a signaling pathway in which SHP-1 acts through CrkII to reshape the pattern of Rap1 activation in the immunological synapse.

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