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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3682-3690.
Prepublished online as a Blood First Edition Paper on August 16, 2007September 12, 2007; DOI 10.1182/blood-2007-03-077628.
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Submitted March 2, 2007
Accepted August 6, 2007
Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin-mediated human T cell adhesion
Haifa Ghandour, Xavier Cullere, Angeles Alvarez, Francis W Luscinskas, and Tanya N Mayadas*
Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
* Corresponding author; email: tmayadas{at}rics.bwh.harvard.edu.
Regulated adhesion of T cells by the integrins LFA-1 and VLA-4 is essential for T cell trafficking. The small GTPase Rap1 is a critical activator of both integrins in murine lymphocytes and T cell lines. Here we examined the contribution of the Rap1 regulatory pathway in integrin activation in primary CD3+ human T cells. We demonstrate that inactivation of Rap1 GTPase in human T cells by expression of SPA1 or Rap1GAP blocked SDF-1 -stimulated LFA-1-ICAM-1 interactions and LFA-1 affinity modulation but unexpectedly, did not significantly affect binding of VLA-4 to its ligand VCAM-1. Importantly, silencing of the Rap1 guanine exchange factor CalDAG-GEFI inhibited SDF-1 and PMA induced adhesion to ICAM-1, while having no effect on adhesion to VCAM-1. Pharmacological inhibition of Phospholipase C (PLC) blocked Rap1 activation and inhibited cell adhesion and polarization on ICAM-1 and VCAM-1. Protein kinase C (PKC) inhibition led to enhanced levels of active Rap1 concomitantly with increased T cell binding to ICAM-1, while adhesion to VCAM-1 was reduced. Thus, PLC/CalDAG-GEFI regulation of Rap1 is selectively required for chemokine and PMA induced LFA-1 activation in human T cells while alternate PLC and PKC dependent mechanisms are involved in the regulation of VLA-4.
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