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Src Homology 2-Domain Containing Leukocyte-Specific Phosphoprotein of 76 kDa Is Mandatory for TCR-Mediated Inside-Out Signaling, but Dispensable for CXCR4-Mediated LFA-1 Activation, Adhesion, and Migration of T Cells¹

Jessica Horn,^2* Xiaoqian Wang,^2* Peter Reichardt,^* Theresia E. Stradal, Nicole Warnecke,^* Luca Simeoni,^* Matthias Gunzer,^* Deborah Yablonski, Burkhart Schraven,^3* and Stefanie Kliche^3*

^*Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany; Signaling and Motility Group, Helmholtz Center for Infection Research, Braunschweig, Germany; and Rappaport Faculty of Medicine and Technion-Israel Institute of Technology, Haifa, Israel

Engagement of the TCR or of chemokine receptors such as CXCR4 induces adhesion and migration of T cells via so-called inside-out signaling pathways. The molecular processes underlying inside-out signaling events are as yet not completely understood. In this study, we show that TCR- and CXCR4-mediated activation of integrins critically depends on the membrane recruitment of the adhesion- and degranulation-promoting adapter protein (ADAP)/Src kinase-associated phosphoprotein of 55 kDa (SKAP55)/Rap1-interacting adapter protein (RIAM)/Rap1 module. We further demonstrate that the Src homology 2 domain containing leukocyte-specific phosphoprotein of 76 kDa (SLP76) is crucial for TCR-mediated inside-out signaling and T cell/APC interaction. Besides facilitating membrane recruitment of ADAP, SKAP55, and RIAM, SLP76 regulates TCR-mediated inside-out signaling by controlling the activation of Rap1 as well as Rac-mediated actin polymerization. Surprisingly, however, SLP76 is not mandatory for CXCR4-mediated inside-out signaling. Indeed, both CXCR4-induced T cell adhesion and migration are not affected by loss of SLP76. Moreover, after CXCR4 stimulation, the ADAP/SKAP55/RIAM/Rap1 module is recruited to the plasma membrane independently of SLP76. Collectively, our data indicate a differential requirement for SLP76 in TCR- vs CXCR4-mediated inside-out signaling pathways regulating T cell adhesion and migration.

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 supported by Deutsche Forschungsgemeinschaft Grants GRK1167 and KL-1295/5-1 (to B.S. and S.K.) and by German-Israeli Foundation for Scientific Research and Development Grant (to D.Y. and B.S.).

² J.H. and X.W. are first authors.

³ Address correspondence and reprint requests to Drs. Stefanie Kliche or Burkhart Schraven, Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany. E-mail address: stefanie.kliche{at}med.ovgu.de

⁴ Abbreviations used in this paper: SLP76, Src homology 2-domain containing leukocyte-specific phosphoprotein of 76 kDa; ADAP, adhesion- and degranulation-promoting adapter protein; IS, immunological synapse; Itk, IL-2-inducible T cell kinase; LAT, linker for activation of T cells; PFA, paraformaldehyde; PLC1, phospholipase C1; RIAM, Rap1-interacting adapter protein; RNAi, RNA interference; SA, superantigen; sh, small hairpin RNA; siRNA, small interfering RNA; SKAP55, Src kinase-associated phosphoprotein of 55 kDa; TRITC, tetramethylrhodamine isothiocyanate.

⁵ The online version of this article contains supplemental material.