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¹ Experimentelle Rheumatologie, Medizinische Klinik, Charité, Humboldt-Universitaet, 10117 Berlin, Germany
² Mukosale Immunitaet, Gesellschaft für Biotechnologische Forschung, 38124 Braunschweig, Germany
³ Institut fuer Pathologie, Universitaet Jena, 07743 Jena, Germany
⁴ Universitaet Greifswald, 17487 Greifswald, Germany
⁵ Institute of Human Genetics, Polish Academy of Sciences, 60479 Poznan, Poland
⁶ Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany

Address correspondence to Jochen Huehn, c/o DRFZ, Humboldt-Universitaet, Schumannstr. 21/22, 10117 Berlin, Germany. Phone: 49-30-28460-796; Fax: 49-30-28460-656; email: Huehn{at}drfz.de

Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin _Eß₇ discriminates distinct subsets of murine CD4⁺ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. _E^-CD25⁺ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, _E-positive subsets (CD25⁺ and CD25^-) displayed an effector/memory phenotype expressing high levels of E/P-selectin–binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, _E-expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

Key Words: CD103 • CD25 • lymphocyte migration • chemokines • inflammation

The online version of this article includes supplemental material.

Abbreviations used in this paper: DNFB, 2,4-dinitrofluorobenzene; ICOS, inducible costimulator; mBSA, methylated BSA; SA, streptavidin; TREC, T cell receptor excision circle; Treg, regulatory T cell.

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• Li, L., Greenwald, R. J., Lafuente, E. M., Tzachanis, D., Berezovskaya, A., Freeman, G. J., Sharpe, A. H., Boussiotis, V. A. (2005). Rap1-GTP Is a Negative Regulator of Th Cell Function and Promotes the Generation of CD4+CD103+ Regulatory T Cells In Vivo. J. Immunol. 175: 3133-3139 [Abstract] [Full Text]  
• Grueter, B., Petter, M., Egawa, T., Laule-Kilian, K., Aldrian, C. J., Wuerch, A., Ludwig, Y., Fukuyama, H., Wardemann, H., Waldschuetz, R., Moroy, T., Taniuchi, I., Steimle, V., Littman, D. R., Ehlers, M. (2005). Runx3 Regulates Integrin {alpha}E/CD103 and CD4 Expression during Development of CD4-/CD8+ T Cells. J. Immunol. 175: 1694-1705 [Abstract] [Full Text]  
• Suffia*, I., Reckling*, S. K., Salay*, G., Belkaid*, Y. (2005). A Role for CD103 in the Retention of CD4+CD25+ Treg and Control of Leishmania major Infection. J. Immunol. 174: 5444-5455 [Abstract] [Full Text]  
• Lee, B. P.-L., Mansfield, E., Hsieh, S.-C., Hernandez-Boussard, T., Chen, W., Thomson, C. W., Ford, M. S., Bosinger, S. E., Der, S., Zhang, Z.-x., Zhang, M., Kelvin, D. J., Sarwal, M. M., Zhang, L. (2005). Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival. J. Immunol. 174: 4535-4544 [Abstract] [Full Text]  
• Kleinewietfeld, M., Puentes, F., Borsellino, G., Battistini, L., Rotzschke, O., Falk, K. (2005). CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset. Blood 105: 2877-2886 [Abstract] [Full Text]  
• van Bilsen, J. H. M., van Dongen, H., Lard, L. R., van der Voort, E. I. H., Elferink, D. G., Bakker, A. M., Miltenburg, A. M. M., Huizinga, T. W. J., de Vries, R. R. P., Toes, R. E. M. (2004). Functional regulatory immune responses against human cartilage glycoprotein-39 in health vs. proinflammatory responses in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 101: 17180-17185 [Abstract] [Full Text]  
• Bruder, D., Westendorf, A. M., Geffers, R., Gruber, A. D., Gereke, M., Enelow, R. I., Buer, J. (2004). CD4 T Lymphocyte-mediated Lung Disease: Steady State between Pathological and Tolerogenic Immune Reactions. Am. J. Respir. Crit. Care Med. 170: 1145-1152 [Abstract] [Full Text]  
• Taylor, P. A., Panoskaltsis-Mortari, A., Swedin, J. M., Lucas, P. J., Gress, R. E., Levine, B. L., June, C. H., Serody, J. S., Blazar, B. R. (2004). L-Selectinhi but not the L-selectinlo CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood 104: 3804-3812 [Abstract] [Full Text]  
• Dujardin, H. C., Burlen-Defranoux, O., Boucontet, L., Vieira, P., Cumano, A., Bandeira, A. (2004). Regulatory potential and control of Foxp3 expression in newborn CD4+ T cells. Proc. Natl. Acad. Sci. USA 101: 14473-14478 [Abstract] [Full Text]  

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