CCR7 and its ligands: balancing immunity and tolerance

Abstract

A key feature of the immune system is its ability to induce protective immunity against pathogens while maintaining tolerance towards self and innocuous environmental antigens. Recent evidence suggests that by guiding cells to and within lymphoid organs, CC-chemokine receptor 7 (CCR7) essentially contributes to both immunity and tolerance. This receptor is involved in organizing thymic architecture and function, lymph-node homing of naive and regulatory T cells via high endothelial venules, as well as steady state and inflammation-induced lymph-node-bound migration of dendritic cells via afferent lymphatics. Here, we focus on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

“…Immature DC express amongst others the chemokine receptors CCR2 and CCR5 and use them to infiltrate allografts, where they capture foreign antigens, thereby inducing maturation of DC. The maturation process leads to a downregulation of the pro-inflammatory chemokine receptors and in parallel to an upregulation of CCR7 [38]. Mature DC migrate via CCR7 to the draining lymph node, where they stimulate naïve T cells.…”

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]).…”

“…This occurs either from lymph-borne antigen capture by B cells and lymph node resident APCs [2][3][4], or by the more classical route of peripherally-activated DC migration to the LN and activation of resident T cells [5]. Lymph nodes are also important centers for the maintenance of tolerance to self-antigens [4,[6][7][8][9].…”

Visualizing dendritic cell migration within the skin

“…Following the generation of CCR7-deWcient mice, it soon became apparent that CCR7 was essential for DC mobilization to LNs from peripheral tissues (Forster et al 1999;Ohl et al 2004). CCR7 recognizes the ligands CCL19 and CCL21, which together coordinate the traYcking of both DCs and T cells to, and within, secondary lymphoid organs under both steady-state and inXammatory conditions (reviewed by Forster et al 2008). In mice, there exist two copies of CCL21: CCL21-Leu (which contains a leucine residue at position 65) and CCL21-Ser (which contains a serine residue in place of the leucine residue) (Chen et al 2002).…”