Naive T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis.
Naive T cells are usually excluded from nonlymphoid tissues. Only when such tertiary tissues are subjected to chronic inflammation, such as in some (but not all) autoimmune diseases, are naive T cells recruited to these sites. We show that the CCR7 ligand CC chemokine ligand (CCL)21 is sufficient for attracting naive T cells into tertiary organs. We performed intravital microscopy of cremaster muscle venules in T-GFP mice, in which naive T cells express green fluorescent protein (GFP). GFP(+) cells underwent selectin-dependent rolling, but no firm adherence (sticking). Superfusion with CCL21, but not CXC chemokine ligand 12, induced integrin-dependent sticking of GFP(+) cells. Moreover, CCL21 rapidly elicited accumulation of naive T cells into sterile s.c. air pouches. Interestingly, a second CCR7 ligand, CCL19, triggered T cell sticking in cremaster muscle venules, but failed to induce extravasation in air pouches. Immunohistochemistry studies implicate ectopic expression of CCL21 as a mechanism for naive T cell traffic in human autoimmune diseases. Most blood vessels in tissue samples from patients with rheumatoid arthritis (85 +/- 10%) and ulcerative colitis (66 +/- 1%) expressed CCL21, and many perivascular CD45RA(+) naive T cells were found in these tissues, but not in psoriasis, where CCL21(+) vessels were rare (17 +/- 1%). These results identify endothelial CCL21 expression as an important determinant for naive T cell migration to tertiary tissues, and suggest the CCL21/CCR7 pathway as a therapeutic target in diseases that are associated with naive T cell recruitment.
Weninger
Wolfgang
W
The Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA. uva@cbr.med.harvard.edu
Carlsen
Hege S
HS
Goodarzi
Mahmoud
M
Moazed
Farzad
F
Crowley
Maura A
MA
Baekkevold
Espen S
ES
Cavanagh
Lois L
LL
von Andrian
Ulrich H
UH
D000328:Adult; D000368:Aged; D000388:Air; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000096:biosynthesis / Q000502:physiology*; D002648:Child; D003093:Colitis, Ulcerative / Q000276:immunology / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins; D006801:Humans; D016130:Immunophenotyping; D007279:Injections, Subcutaneous; D007399:Interphase / Q000235:genetics / Q000276:immunology*; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D014699:Venules / Q000166:cytology / Q000276:immunology
C515478:CCL21 protein, human; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins