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Dynamic Development of Homing Receptor Expression and Memory Cell Differentiation of Infant CD4⁺CD25^high Regulatory T Cells¹

Hanna Grindebacke^2,*, Hanna Stenstad, Marianne Quiding-Järbrink, Jesper Waldenström^*, Ingegerd Adlerberth, Agnes E. Wold and Anna Rudin^*

^* Department of Rheumatology and Inflammation Research, Department of Microbiology and Immunology, Department of Clinical Bacteriology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden

Migration of CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Treg) is important for suppressing immune responses in different tissues. Previous studies show that the majority of Treg at birth express gut homing receptor ₄β₇ and that only few express CCR4, while the reverse pattern is found in adults. The age at which homing receptor switch occurs in vivo is not known. In this study, we show, in a prospective study of human infants from birth to 3 years of age, that homing receptor switch from ₄β₇ to CCR4 commences between 1 1/2 and 3 years of age and that Treg at that age also had started their switch to a memory phenotype. The majority of naive Treg express ₄β₇ in infants but not in adults, while the majority of memory Treg express CCR4 both infants and adults. The homing receptor expression on Treg corresponds to their actual migration properties, because Treg from cord blood migrate foremost toward the gut-associated chemokine CCL25. CD4⁺FOXP3⁺ T cell numbers increase rapidly in the circulation during the first days of life indicating conversion to suppressive Treg from CD25^high Treg precursors. These findings suggest that the gut is the primary site of Treg stimulation to exogenous Ags during the first 18 mo of life and that homing receptor switch toward a more extra-intestinal phenotype occurs thereafter.

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 funded by the Swedish Research Council (Grant K2006-745X-14455-05-3), by the Vårdal Foundation, by the Health & Medical Care Committee of the Region Västra Götaland, by Medi-SAM (to A.L.F.), by Frimurare Barnhusdirektionen, by the Swedish Asthma and Allergy Association, and by Åke Wibergs stiftelse.

² Address correspondence and reprint requests to Hanna Grindebacke, Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Göteborg, Sweden. E-mail address: hanna.grindebacke{at}rheuma.gu.se

³ Abbreviation used in this paper: Treg, regulatory T cell.