期刊
BLOOD
卷 110, 期 10, 页码 3682-3690出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-03-077628
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- NHLBI NIH HHS [P01 HL036028] Funding Source: Medline
Regulated adhesion of T cells by the integrins LFA-1 (lymphocyte function-associated antigen-1) and VLA-4 (very late antigen-4) is essential for T-cell trafficking. The small GTPase Rapt 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 stromal cell-derived factor-lot (SDF-1 alpha)-stimulated LFA-1-ICAM-1 (intercellular adhesion molecule-1) interactions and LFA-1 affinity modulation but unexpectedly did not significantly affect binding of VLA-4 to its ligand VCAM-1 (vascular cell adhesion molecule 1). Importantly, silencing of the Rapt guanine exchange factor CaIDAG-GEM inhibited SDIF-1 alpha- and phorbol 12-myristate 13-acetate (PMA)-induced adhesion to ICAM-1 while having no effect on adhesion to VCAM-1. Pharmacologic 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, whereas adhesion to VCAM-1 was reduced. Thus, PLC/CaIDAG-GEFI regulation of Rap is selectively required for chemokine- and PMA-induced LFA-1 activation inhuman T cells, whereas alternate PLC- and PKC-dependent mechanisms are involved in the regulation of VLA-4.
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