Weninger Wolfgang, Carlsen Hege S, Goodarzi Mahmoud, Moazed Farzad, Crowley Maura A, Baekkevold Espen S, Cavanagh Lois L, von Andrian Ulrich H
The Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2003 May 1;170(9):4638-48. doi: 10.4049/jimmunol.170.9.4638.
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.
初始T细胞通常不会进入非淋巴组织。只有当这些三级组织受到慢性炎症影响时，比如在某些（但并非所有）自身免疫性疾病中，初始T细胞才会被招募到这些部位。我们发现，CCR7配体CC趋化因子配体（CCL）21足以将初始T细胞吸引到三级器官中。我们对T-GFP小鼠的提睾肌小静脉进行了活体显微镜观察，在这些小鼠中，初始T细胞表达绿色荧光蛋白（GFP）。GFP(+)细胞经历了依赖选择素的滚动，但没有牢固黏附（黏着）。用CCL21而非CXC趋化因子配体12进行超灌注，可诱导GFP(+)细胞发生依赖整合素的黏着。此外，CCL21能迅速促使初始T细胞在无菌皮下气囊中聚集。有趣的是，另一种CCR7配体CCL19可引发提睾肌小静脉中的T细胞黏着，但未能诱导其在气囊中渗出。免疫组织化学研究表明，CCL21的异位表达是人类自身免疫性疾病中初始T细胞迁移的一种机制。类风湿性关节炎患者（85±10%）和溃疡性结肠炎患者（66±1%）组织样本中的大多数血管表达CCL21，并且在这些组织中发现了许多血管周围的CD45RA(+)初始T细胞，但在银屑病患者的组织中未发现，银屑病患者组织中CCL21(+)血管很少（17±1%）。这些结果确定了内皮细胞CCL21的表达是初始T细胞迁移至三级组织的一个重要决定因素，并表明CCL21/CCR7通路可作为与初始T细胞招募相关疾病的治疗靶点。
