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Blood, 1 February 2007, Vol. 109, No. 3, pp. 886-895.
Prepublished online as a Blood First Edition Paper on October 3, 2006; DOI 10.1182/blood-2006-03-013532.
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Submitted March 29, 2006
Accepted September 11, 2006
CCR7 deficiency causes ectopic lymphoid neogenesis and disturbed mucosal tissue integrity
Uta E. Hoepken*, Antje M. Wengner, Christoph Loddenkemper, Harald Stein, Markus M. Heimesaat, Armin Rehm, and Martin Lipp
Max-Delbrueck-Center for Molecular Medicine, Germany
Charite-Universitaetsmedizin Berlin, Germany
* Corresponding author; email: uhoepken{at}mdc-berlin.de.
Homeostatic trafficking of lymphocytes through extralymphoid tissues has been recently observed and a potential role in immune surveillance and the establishment of peripheral tolerance is considered. However, the mechanisms regulating lymphocyte recirculation through peripheral tissues under non-inflammatory conditions are not well understood. Here, we demonstrate that the chemokine receptor CCR7 controls not only lymphocyte trafficking to and within secondary lymphoid organs, but also homeostatic recirculation of T and B lymphocytes through non-lymphoid tissues. Lack of CCR7 results in a massive accumulation of lymphocytes in epithelial tissues. In particular, the gastrointestinal mucosal tissue of CCR7-/- mice is highly permissive for the formation of lymphoid aggregates, which develop into ectopic follicular structures with major topological characteristics of lymph nodes. Flow cytometry analysis of CD4+ T cells derived from ectopic follicles revealed that CD44hiCD62Llo effector memory T cells predominate in the gastric lymphoid aggregates. In aged mice, lack of CCR7 induced age-dependent histomorphological changes in the stomach with profound cystic hyperplasia and an increased rate of mucosal proliferation resembling Menetrier's disease. Thus, CCR7 regulates the cellular organization of visceral tissue by governing life-long recirculation of naive and memory lymphocytes under homeostatic conditions.
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