Naive T Cell Recruitment to Nonlymphoid Tissues: A Role for Endothelium-Expressed CC Chemokine Ligand 21 in Autoimmune Disease and Lymphoid Neogenesis

Abstract

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.

Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis

“…We observed, in keeping with previous reports [20,21], that CCL21 expression was associated with scattered or clustered cells (Fig. 6A, B) as well as with vascular structures (Fig.…”

“…Some of these scattered nonvascular CCL21 + cells, whose phenotype is currently under investigation, appeared irregular in shape, with prolonged cytoplasmic processes (not shown). Although it has been suggested that CCL21 may play a role in ectopic lymphoid neogenesis in RA synovium [20,21], no comparative analysis between the vascular and nonvascular pattern was carried out in those studies. Our systematic in situ analysis demonstrated that nonvascular CCL21-producing cells were specifically associated with lymphoid aggregates; they were only rarely or were not detected in the sublining stroma devoid of a consistent mononuclear infiltrate.…”

“…The concept that CXCL13 and CCL21 may also be involved in human ectopic lymphoid tissue organization is supported by their detection in several chronic inflammatory conditions including rheumatoid arthritis (RA) [17][18][19][20][21][22]. An attempt to define the functional roles of CXCL13 and CCL21 in synovial lymphoid neogenesis in RA was made by Takemura et al [18], who examined the relationship between mRNA levels of CXCL13 and CCL21 on homogenized synovial tissues and the organizational pattern of the inflammatory infiltrate.…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…). Structurally mature ELFs are not, however, seen in skin conditions despite local expression of Ccl21 , which suggests that the immune setting and the interaction of the stromal compartment with resident and infiltrating cells has to be conducive for ELF development to occur 56, 57. This may reflect differences in innate sensing responses or a differential stromal response to chemokines and cytokines necessary for the initiation, expansion and maintenance of tissue ELFs.…”

The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells

“…As a control, mice were injected in the contralateral inguinal mammary fat pad with vehicle alone as previously reported (38,39).…”