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Sequential Cooperation of CD2 and CD48 in the Buildup of the Early TCR Signalosome¹

Arshad Muhammad^*, Herbert B. Schiller^*, Florian Forster^*, Paul Eckerstorfer^*, Rene Geyeregger, Vladimir Leksa^*,, Gerhard J. Zlabinger, Maria Sibilia, Alois Sonnleitner^¶, Wolfgang Paster^2,* and Hannes Stockinger^2,*

^* Department of Molecular Immunology, Centre for Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria; Institute of Cancer Research, Medical University Vienna, Vienna, Austria; Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Slovak Republic; Institute of Immunology, Medical University of Vienna, Vienna, Austria; and ^¶ Center for Biomedical Nanotechnology, Upper Austrian Research, Linz, Austria

The buildup of TCR signaling microclusters containing adaptor proteins and kinases is prerequisite for T cell activation. One hallmark in this process is association of the TCR with lipid raft microdomains enriched in GPI-proteins that have potential to act as accessory molecules for TCR signaling. In this study, we show that GPI-anchored CD48 but not CD59 was recruited to the immobilized TCR/CD3 complex upon activation of T cells. CD48 reorganization was vital for T cell IL-2 production by mediating lateral association of the early signaling component linker for activated T cells (LAT) to the TCR/CD3 complex. Furthermore, we identified CD2 as an adaptor linking the Src protein tyrosine kinase Lck and the CD48/LAT complex to TCR/CD3: CD2 associated with TCR/CD3 upon T cell activation irrespective of CD48 expression, while association of CD48 and LAT with the TCR/CD3 complex depended on CD2. Consequently, our data indicate that CD2 and CD48 cooperate hierarchically in the buildup of the early TCR signalosome; CD2 functions as the master switch recruiting CD48 and Lck. CD48 in turn shuttles the transmembrane adapter molecule LAT.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by the GEN-AU program of the Austrian Federal Ministry of Science and Research, the PhD program Cell Communication in Health and Disease, the Competence Centre for Biomolecular Therapeutics and the Higher Education Commission of Pakistan.

² Address correspondence and reprint requests to Dr. Wolfgang Paster or Dr. Hannes Stockinger, Centre for Physiology, Pathophysiology and Immunology, Medical University of Vienna, Lazarettgasse 19, Vienna, Austria. E-mail address: wolfgang.paster{at}meduniwien.ac.at or hannes.stockinger{at}meduniwien.ac.at

³ Abbreviations used in this paper: LAT, linker for activated T cell; IS, immunological synapse; SPSP, solid phase signalosome precipitation; AF, Alexa Fluor; shRNA, short hairpin RNA; SEE, staphylococcus enterotoxin E.