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* Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, and
Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129
The chemokine IFN-
-inducible protein of 10 kDa (IP-10; CXCL10) plays an important role in the recruitment of activated T lymphocytes into sites of inflammation by interacting with the G protein-coupled receptor CXCR3. IP-10, like other chemokines, forms oligomers, the role of which has not yet been explored. In this study, we used a monomeric IP-10 mutant to elucidate the functional significance of oligomerization. Although monomeric IP-10 had reduced binding affinity for CXCR3 and heparin, it was able to induce in vitro chemotaxis of activated T cells with the same efficacy as wild-type IP-10. However, monomeric IP-10 was unable to induce recruitment of activated CD8+ T cells into the airways of mice after intratracheal instillation. Use of a different IP-10 mutant demonstrated that this inability was due to lack of oligomerization rather than reduced CXCR3 or heparin binding. Molecular imaging demonstrated that both wild-type and monomeric IP-10 were retained in the lung after intratracheal instillation. However, in vitro binding assays indicated that wild-type, but not monomeric, IP-10 was retained on endothelial cells and could induce transendothelial chemotaxis of activated T cells. We therefore propose that oligomerization of IP-10 is required for presentation on endothelial cells and subsequent transendothelial migration, an essential step for lymphocyte recruitment in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant RO1-CA69212 (to A.D.L.) and R24-CA92782 (to R.W.).
2 Address correspondence and reprint requests to Dr. Andrew D. Luster, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129. E-mail address: luster.andrew{at}mgh.harvard.edu
3 Abbreviations used in this paper: IP-10, IFN--inducible protein of 10 kDa; GAG, glycosaminoglycan; HMEC, human microvascular endothelial cells; CHO, Chinese hamster ovary; BAL, bronchoalveolar lavage; DTPA, diethylenetriaminepentaacetic; CT, computed tomography; SPECT, single-photon emission CT; Sulfo-EGS, sulfo-ethylene glycolbis(sulfosuccinimidylsuccinate); BS3, bis(sulfosuccinimidyl)suberate.
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