Published online before print August 28, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.080052

Accepted for publication July 7, 2008.

Article

Cellular Players and Role of Selectin Ligands in Leukocyte Recruitment in a T-Cell-Initiated Delayed-Type Hypersensitivity Reaction

Cornelia Doebis^*, Kerstin Siegmund^*, Christoph Loddenkemper, John B. Lowe, Andrew C. Issekutz, Alf Hamann^*, Jochen Huehn^*, and Uta Syrbe^*¶@

From the Départemente of Experimentelle Rheumatologie,* Charité, Campus Mitte, Berlin, Germany; the Institute of Pathylogy/Research Center ImmunoSciences, and the Medizinische Klinik I,^¶ Charité, Campus Benjamin Franklin, Berlin, Germany; the Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio; and the Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Canada

^@ To whom correspondence should be addressed. E-mail: uta.syrbe{at}charite.de.

	Abstract

Delayed-type hypersensitivity (DTH) reactions are characterized by a strong cellular infiltrate, including neutrophils, macrophages, and T lymphocytes. In all these cell types, both E- and P-selectin-dependent adhesion pathways play a significant role in recruitment into the inflamed skin. Accordingly, inhibition of selectin-mediated interactions (eg, by antibodies) results in impairment of acute DTH reactions. However, whether inhibition of a specific cell type is responsible for the anti-inflammatory effect or whether all leukocytes are affected remains unclear. To address this question, we used fucosyltransferase-VII knockout mice that lack functional selectin ligands as either donors or recipients in a DTH model elicited by Th1 cell and antigen transfer. We found that selectin-mediated adhesion is required by Th1 effector cells to enter the DTH reaction site and, additionally, to elicit the DTH reaction. On the other hand, elimination of selectin binding in the recipient's neutrophils and macrophages by use of fucosyltransferase-deficient mice receiving wild-type Th1 effector cells resulted in a strongly reduced infiltration of neutrophils and macrophages but unimpaired footpad swelling. These findings demonstrate a major role for both E- and P-selectin in the recruitment of different leukocyte cell types. However, only the presence of selectin ligands on T cells was critical for the inflammatory reaction. These findings reveal T cells as the predominant targets for selectin blockade that aim to suppress skin inflammation.