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© The Rockefeller University Press, 0021-9525/1997//1349 $5.00
The Journal of Cell Biology, Volume 139, Number 5, , 1997 1349-1360

Article

Multistep Navigation and the Combinatorial Control of Leukocyte Chemotaxis



Ellen F. Foxman, James J. Campbell, and Eugene C. Butcher

Laboratory of Immunology and Vascular Biology, Department of Pathology, and the Digestive Disease Center, Department of Medicine, Stanford University Medical School, Stanford, California 94305-5324; and the Center for Molecular Biology and Medicine, Foothill Research Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304

Cells migrating within tissues may encounter multiple chemoattractant signals in complex spatial and temporal patterns. To understand leukocyte navigation in such settings, we have explored the migratory behavior of neutrophils in model scenarios where they are presented with two chemoattractant sources in various configurations. We show that, over a wide range of conditions, neutrophils can migrate "down" a local chemoattractant gradient in response to a distant gradient of a different chemoattractant. Furthermore, cells can chemotax effectively to a secondary distant agonist after migrating up a primary gradient into a saturating, nonorienting concentration of an initial attractant. Together, these observations suggest the potential for cells' step-by-step navigation from one gradient to another in complex chemoattractant fields. The importance of such sequential navigation is confirmed here in a model system in which neutrophil homing to a defined domain (a) requires serial responses to agonists presented in a defined spatial array, and (b) is a function of both the agonist combination and the sequence in which gradients are encountered. We propose a multistep model of chemoattractant-directed migration, which requires that leukocytes display multiple chemoattractant receptors for successful homing and provides for combinatorial determination of microenvironmental localization.

Abbreviations used in this paper: EC50, 50% effective concentration; fMLP, N-formyl peptide fMet-Leu-Phe; IL-8, interleukin-8; LTB4, leuko-triene B4.

Address all correspondence to E.F. Foxman, c/o Eugene C. Butcher, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324. Tel.: (650) 852-3369. Fax: (650) 858-3986.


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