CCR7 deficiency causes ectopic lymphoid neogenesis and disturbed mucosal tissue integrity.
Homeostatic trafficking of lymphocytes through extralymphoid tissues has been recently observed, and a potential role in immune surveillance and the establishment of peripheral tolerance are considered. However, the mechanisms regulating lymphocyte recirculation through peripheral tissues under noninflammatory 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 migration of T and B lymphocytes through nonlymphoid 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 topologic 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 histomorphologic changes in the stomach with profound cystic hyperplasia and an increased rate of mucosal proliferation resembling Menetrier disease. Thus, CCR7 regulates the cellular organization of visceral tissue by governing life-long recirculation of naive and memory lymphocytes under homeostatic conditions.
Höpken
Uta E
UE
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. uhoepken@mdc-berlin.de
Wengner
Antje M
AM
Loddenkemper
Christoph
C
Stein
Harald
H
Heimesaat
Markus M
MM
Rehm
Armin
A
Lipp
Martin
M
D000375:Aging; D000818:Animals; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte; D005758:Gastritis, Hypertrophic; D006965:Hyperplasia; D016130:Immunophenotyping; D007413:Intestinal Mucosa / Q000473:pathology*; D008214:Lymphocytes / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000172:deficiency*
C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D019707:Receptors, Chemokine