Heterotropic modulation of selectin affinity by allosteric antibodies affects leukocyte rolling

Selectins are a family of adhesion receptors designed for efficient leukocyte tethering to the endothelium under shear. As a key property to resist premature bond disruption, selectin adhesiveness is enhanced by tensile forces that promote the conversion of a bent into an extended conformation of th...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2014-02, Vol.192 (4), p.1862-1869
Main Authors: Riese, Sebastian B, Kuehne, Christian, Tedder, Thomas F, Hallmann, Rupert, Hohenester, Erhard, Buscher, Konrad
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Antibodies - immunology
Antibodies, Monoclonal - immunology
Cell Adhesion - immunology
Cell Line
Humans
Jurkat Cells
Leukocyte Rolling - immunology
Neutrophils - immunology
Selectins - immunology
Selectins - metabolism
Sequence Alignment
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Summary:Selectins are a family of adhesion receptors designed for efficient leukocyte tethering to the endothelium under shear. As a key property to resist premature bond disruption, selectin adhesiveness is enhanced by tensile forces that promote the conversion of a bent into an extended conformation of the N-terminal lectin and epidermal growth factor-like domains. Conformation-specific Abs have been invaluable in deciphering the activation mechanism of integrins, but similar reagents are not available for selectins. In this study, we show that the anti-human L-selectin mAbs DREG-55 and LAM1-5 but not DREG-56, DREG-200, or LAM1-1 heterotropically modulate adhesion presumably by stabilizing the extended receptor conformation. Force-free affinity assays, flow chamber, and microkinetic studies reveal a ligand-specific modulation of L-selectin affinity by DREG-55 mAb, resulting in a dramatic decrease of rolling velocity under flow. Furthermore, secondary tethering of polymorphonuclear cells was blocked by DREG-200 but significantly boosted by DREG-55 mAb. The results emphasize the need for a new classification for selectin Abs and introduce the new concept of heterotropic modulation of receptor function.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1302147