The Cc Chemokine Thymus-Derived Chemotactic Agent 4 (Tca-4, Secondary Lymphoid Tissue Chemokine, 6ckine, Exodus-2) Triggers Lymphocyte Function–Associated Antigen 1–Mediated Arrest of Rolling T Lymphocytes in Peripheral Lymph Node High Endothelial Venules

Abstract

T cell homing to peripheral lymph nodes (PLNs) is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial tethering and rolling via L-selectin, firm adhesion of T cells requires rapid upregulation of lymphocyte function–associated antigen 1 (LFA-1) adhesiveness by a previously unknown pathway that activates a Gαi-linked receptor. Here, we used intravital microscopy of murine PLNs to study the role of thymus-derived chemotactic agent (TCA)-4 (secondary lymphoid tissue chemokine, 6Ckine, Exodus-2) in homing of adoptively transferred T cells from T-GFP mice, a transgenic strain that expresses green fluorescent protein (GFP) selectively in naive T lymphocytes (TGFP cells). TCA-4 was constitutively presented on the luminal surface of HEVs, where it was required for LFA-1 activation on rolling TGFP cells. Desensitization of the TCA-4 receptor, CC chemokine receptor 7 (CCR7), blocked TGFP cell adherence in wild-type HEVs, whereas desensitization to stromal cell–derived factor (SDF)-1α (the ligand for CXC chemokine receptor 4 [CXCR4]) did not affect TGFP cell behavior. TCA-4 protein was not detected on the luminal surface of PLN HEVs in plt/plt mice, which have a congenital defect in T cell homing to PLNs. Accordingly, TGFP cells rolled but did not arrest in plt/plt HEVs. When TCA-4 was injected intracutaneously into plt/plt mice, the chemokine entered afferent lymph vessels and accumulated in draining PLNs. 2 h after intracutaneous injection, luminal presentation of TCA-4 was detectable in a subset of HEVs, and LFA-1–mediated TGFP cell adhesion was restored in these vessels. We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs. This study also highlights a hitherto undocumented role for chemokines contained in afferent lymph, which may modulate leukocyte recruitment in draining PLNs.

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.…”

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]).…”

Primary immune surveillance: some like it hot

“…Activation of lymphocytes to induce firm arrest is mediated by tissue-specific chemokines displayed on endothelial surfaces [17]. In mice, HEVs have the ability to produce and display CCL21, the chemokine primarily associated with naïve lymphocyte activation [18,19]. In a truly restricted fashion, CCL21 has the ability to only interact with its specific receptor namely, CCR7, which is uniformly found on naïve and central memory T cells.…”