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Molecular and Cellular Biology, October 2007, p. 6863-6875, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00556-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Functional Defects of SKAP-55-Deficient T Cells Identify a Regulatory Role for the Adaptor in LFA-1 Adhesion

Cell Signalling Section, Division of Immunology, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP,¹ Molecular Immunology Section, Department of Immunology, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom²

Received 29 March 2007/ Returned for modification 1 May 2007/ Accepted 17 July 2007

The ADAP-SKAP-55 module regulates T-cell receptor (TCR)-induced integrin clustering and adhesion in T cells. However, it has been unclear whether ADAP and/or SKAP-55 is an effector of the response. ADAP controls SKAP-55 expression such that ADAP^–/– T cells are also deficient in SKAP-55 expression. In this study, we report the phenotype of the SKAP-55-deficient mouse. SKAP-55^–/– T cells retain ADAP expression yet show defects in ß1 and ß2 integrin adhesion, leukocyte function-associated antigen 1 (LFA-1) clustering, production of the cytokines interleukin-2 and gamma interferon, and proliferation. This dependency was also reflected in more-transient conjugation times in response to the superantigen staphylococcal enterotoxin A on dendritic cells and a reduced number of cells with TCR/CD3 microcluster localization at the immunological synapse. SKAP-55^–/– T cells showed the same general impairment of function as ADAP^–/– T cells, indicating that SKAP-55 is an effector of the ADAP-SKAP-55 module. At the same time, the requirement for ADAP and SKAP-55 was not absolute, since a subset of peripheral T cells adhered with loss of expression of either adaptor. Further, dependency on SKAP-55 or ADAP differed with the strength of the TCR signal. As with the ADAP^–/– mouse, SKAP-55-deficient mice showed no major effects on lymphoid development or the appearance of peripheral T cells, B cells, and NK cells. Our findings identify a clear effector role for SKAP-55 in LFA-1 adhesion in peripheral T cells and demonstrate that dependency on SKAP-55 and ADAP differs among T cells and differs with the strength of the TCR signal.

Published ahead of print on 23 July 2007.