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© The Rockefeller University Press, 0021-9525/1997//493 $5.00
The Journal of Cell Biology, Volume 137, Number 2, , 1997 493-508

Article

ICAMs Redistributed by Chemokines to Cellular Uropods as a Mechanism for Recruitment of T Lymphocytes



Miguel Angel del Pozo*, Carlos Cabañas{ddagger}, María C. Montoya*, Ann Ager§, Paloma Sánchez-Mateos||, and Francisco Sánchez-Madrid*

* Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, 28006-Madrid, Spain; {ddagger} Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040-Madrid, Spain; § National Institute for Medical Research, Division of Cellular Immunology, Medical Research Council, London NW7 1AA, United Kingdom; || Servicio de Inmunología, Hospital General Universitario Gregorio Marañón, 28007-Madrid, Spain

The recruitment of leukocytes from the bloodstream is a key step in the inflammatory reaction, and chemokines are among the main regulators of this process. During lymphocyte–endothelial interaction, chemokines induce the polarization of T lymphocytes, with the formation of a cytoplasmic projection (uropod) and redistribution of several adhesion molecules (ICAM-1,-3, CD43, CD44) to this structure. Although it has been reported that these cytokines regulate the adhesive state of integrins in leukocytes, their precise mechanisms of chemoattraction remain to be elucidated. We have herein studied the functional role of the lymphocyte uropod. Confocal microscopy studies clearly showed that cell uropods project away from the cell bodies of adhered lymphocytes and that polarized T cells contact other T cells through the uropod structure. Time-lapse videomicroscopy studies revealed that uropod-bearing T cells were able, through this cellular projection, to contact, capture, and transport additional bystander T cells. Quantitative analysis revealed that the induction of uropods results in a 5–10-fold increase in cell recruitment. Uropod-mediated cell recruitment seems to have physiological relevance, since it was promoted by both CD45R0+ peripheral blood memory T cells as well as by in vivo activated lymphocytes. Additional studies showed that the cell recruitment mediated by uropods was abrogated with antibodies to ICAM-1, -3, and LFA-1, whereas mAb to CD43, CD44, CD45, and L-selectin did not have a significant effect, thus indicating that the interaction of LFA-1 with ICAM-1 and -3 appears to be responsible for this process. To determine whether the increment in cell recruitment mediated by uropod may affect the transendothelial migration of T cells, we carried out chemotaxis assays through confluent monolayers of endothelial cells specialized in lymphocyte extravasation. An enhancement of T cell migration was observed under conditions of uropod formation, and this increase was prevented by incubation with either blocking anti– ICAM-3 mAbs or drugs that impair uropod formation. These data indicate that the cell interactions mediated by cell uropods represent a cooperative mechanism in lymphocyte recruitment, which may act as an amplification system in the inflammatory response.

1. Abbreviations used in this paper: EC, endothelial cells; ECM, extracellular matrix; HEC, high endothelial cells; PBL, peripheral blood lymphocytes; SF, synovial fluid; TIL, tumor infiltrating lymphocytes.

The generous gift of mAbs is gratefully acknowledged to Drs. F.W. Luscinskas, R. Vilella, W.M. Gallatin, C.G. Figdor, T.F. Tedder, and P. Beverley. We thank Dr. N. Hogg for allowing the use of confocal and videomicroscopy facilities of Imperial Cancer Research Foundation (London, UK) and Liz Hirst (National Institute for Medical Research, London, UK) and Dr. Andrew Edwards (Imperial Cancer Research Foundation, London, UK) for technical assistance with confocal microscopy. We thank Dr. J. García-Sancho for excellent immunofluorescence technical advice, Dr. Natividad Longo and Dr. I. González-Alvaro for providing pathologic samples, and Dr. R. González-Amaro for critical reading of the manuscript.

Please address all correspondence to Francisco Sánchez-Madrid, Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Diego de León, 62, 28006-Madrid, Spain. Tel.: 34-1-402-3347; Fax: 34-1-309-2496; E-mail: fsmadrid/princesa{at}hup.es


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