The Role of Chemokines in the Microenvironmental Control of T versus B Cell Arrest in Peyer's Patch High Endothelial Venules

Abstract

Chemokines have been hypothesized to contribute to the selectivity of lymphocyte trafficking not only as chemoattractants, but also by triggering integrin-dependent sticking (arrest) of circulating lymphocytes at venular sites of extravasation. We show that T cells roll on most Peyer's patch high endothelial venules (PP-HEVs), but preferentially arrest in segments displaying high levels of luminal secondary lymphoid tissue chemokine (SLC) (6Ckine, Exodus-2, thymus-derived chemotactic agent 4 [TCA-4]). This arrest is selectively inhibited by functional deletion (desensitization) of CC chemokine receptor 7 (CCR7), the receptor for SLC and for macrophage inflammatory protein (MIP)-3β (EBV-induced molecule 1 ligand chemokine [ELC]), and does not occur in mutant DDD/1 mice that are deficient in these CCR7 ligands. In contrast, pertussis toxin–sensitive B cell sticking does not require SLC or MIP-3β signaling, and occurs efficiently in SLClow/− HEV segments in wild-type mice, and in the SLC-negative HEVs of DDD/1 mice. Remarkably, sites of T and B cell firm adhesion are segregated in PPs, with HEVs supporting B cell accumulation concentrated in or near follicles, the target domain of most B cells entering PPs, whereas T cells preferentially accumulate in interfollicular HEVs. Our findings reveal a fundamental difference in signaling requirements for PP-HEV recognition by T and B cells, and describe an unexpected level of specialization of HEVs that may allow differential, segmental control of lymphocyte subset recruitment into functionally distinct lymphoid microenvironments in vivo.

Absence of Nkx2-3 Homeodomain Transcription Factor Reprograms the Endothelial Addressin Preference for Lymphocyte Homing in Peyer’s Patches

“…In addition to homing receptors on HEVs, lymphocyte homing to PPs also requires recognition of CCL21 and CXCL13 arrest chemokines present on endothelium in T zone and follicleassociated HEVs, respectively (10)(11)(12). Using immunofluorescent labeling, both CCL21 and CXCL13 were detected in PP HEVs of mutant mice (Fig.…”

“…In mesenteric LNs (mLNs) a combined mechanism operates by which MAdCAM-1 and PNAd, both expressed on HEVs, serve as endothelial receptors for extravasation (9). Subsequently, engagement of chemokine receptors CCR7 and CXCR5 and their respective CCL21 and CXCL13 ligands is required for the promotion of integrin-mediated firm adhesion of T and B lymphocytes (10)(11)(12). Thus, the local specialization of vasculature, including the restricted expression of addressin molecules and chemokines by endothelial cells, critically determines lymphocyte homing to secondary lymphoid tissues.…”

Ectopic Expression of the Murine Chemokines CCL21a and CCL21b Induces the Formation of Lymph Node-Like Structures in Pancreas, But Not Skin, of Transgenic Mice

“…Evidence for this has recently been corroborated in skin explant culture models (11,16,50). Alternatively, the ectopic expression of CCL21 in the epithelium may have disrupted the ability of these cells to migrate by desensitizing CCR7 (9,21). Epidermal CCL21 overexpression does not affect the number of dendritic cells in the skin in the steady state, but may be important during infection or inflammation.…”

“…One of these chemokines is CCL21, also known as 6Ckine (3), secondary lymphoid chemokine (4), Exodus-2 (5), and thymus-derived chemotactic agent-4 (6). CCL21 is constitutively expressed by high endothelium venules of lymph nodes and Peyer's patches (7)(8)(9), stromal cells in the T cell zone of secondary lymphoid organs (10), medullary cells of the thymus (6), and lymphatic vessels (8,11).…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…Mice lacking CCR7 show impaired ability to maintain tolerance to peripheral antigens as they develop signs of autoimmunity [70,71]: they exhibit lymphocyte infiltration in peripheral organs, elevated levels of circulating antibodies towards tissue-specific antigens, IgG deposition around the renal glomeruli, and increased susceptibility to inducible diabetes, and they can spontaneously develop chronic autoimmune renal disease [70]. These mice, as well as those lacking CCL19 and CCL21 (plt mice), which lack recognizable T cells zones within all LNs [72][73][74][75][76], can still mount strong cellular immune responses [6]. This is consistent with the mounting evidence that although B cell responses require their residence in functional lymph nodes, T cell immunity apparently does not, and T cells can be activated in the spleen or even liver when lymph nodes are absent or dysfunctional (reviewed in [77]).…”