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CCR7 and its ligands: balancing immunity and tolerance

Key Points

  • Chemokines are a large family of chemotactic cytokines that regulate immune-cell trafficking. The chemokines CC-chemokine ligand 19 (CCL19) and CCL21 are ligands for the CC-chemokine receptor 7 (CCR7).

  • CCR7 is expressed by B cells, mature dendritic cells (DCs) and by several T-cell sub-populations including naive, regulatory and central memory T cells. In non-lymphoid organs CCR7 ligands are expressed on the initial segments of lymphatic vessels. In lymphoid organs they are present on high endothelial venules (HEVs) as well as on various populations of spleen, lymph node and thymic stromal cells.

  • CCR7 and its ligands have a key role in lymphocyte and DC homing to the lymph nodes and intestinal Peyer's patches. In a naturally occurring mouse mutant, paucity of lymph-node T cells (plt/plt), CCL19 and CCL21 are absent in lymphoid organs, whereas one variant of CCL21 is still expressed in non-lymphoid organs. In CCR7-deficient and plt/plt mice, T cells are impaired in lymph-node homing via high endothelial venules. Furthermore, in Ccr7−/− mice, DCs fail to enter initial afferent lymphatic vessels following inflammatory stimuli. Therefore, lymph nodes of CCR7-deficient mice are devoid of naive and regulatory T cells and immunity-inducing DCs. Owing to impaired homing of T cells and DCs, CCR7-deficient and plt/plt mice show delayed immune responses at sites where antigen is limited.

  • CCR7 deficiency also impedes the steady-state migration of DCs from non-lymphoid organs, such as the intestine and lung, into the draining lymph nodes. Such migration of DCs that are laden with innocuous antigen, however, is required for the induction of peripheral tolerance. Within secondary lymphoid organs these DCs present food or environmental antigens to reactive T cells, which leads to their anergy, deletion or conversion into regulatory T cells. Owing to impaired homing of T cells and tolerance-inducing DCs to secondary lymphoid organs, CCR7-deficient mice do not develop tolerance to harmless environmental antigens.

  • The paracortical area of lymph nodes is the major site of the suppressive activity of natural regulatory T cells. In CCR7-deficient mice, regulatory T cells show impaired homing to this location and therefore have a profound defect of their in vivo function. CCR7 and its ligands are also essentially involved in thymus organization, T-cell development and negative selection.

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.

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Figure 1: CCR7 in the induction of tolerance to inhaled antigens.
Figure 2: CCR7 in function of regulatory T cells.
Figure 3: CCR7 in thymocyte migration.

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Acknowledgements

We thank T. Worbs and G. Bernhardt for valuable suggestions on this manuscript. A.R. is supported by the EU 6th Framework Program collaborative grant INNOCHEM (LSHB-CT-2005-518167). R.F. is supported by grants from the German Research Foundation (DFG SFB621-A1, DFG SFB587-B3, DFG SFB566-A14, DFG SFB738-B5). We regret that, owing to space limitations, we could not always adequately quote the work of our colleagues contributing to the field reviewed here.

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Glossary

Regulatory T (TReg) cell

A naturally occurring subtype of regulatory T cell, which develops in the thymus and regulates self-reactive T cells in the periphery. TReg cells are characterized by the expression of CD25 (interleukin-2 receptor α-chain) and the transcription factor FOXP3 (forkhead box P3).

Paucity of lymph-node T cells (plt/plt) mice

A spontaneously occurring mutant strain that lost the expression of the CC-chemokine receptor 7 (CCR7)-ligands CC-chemokine ligand (CCL19) and the lymphoid tissue form of CCL21 (CCL21-Ser). Lack of these chemokines results in defective thymic architecture and function, as well as impaired migration of CCR7-expressing T cells and dendritic cells into lymphoid organs, leading to their hypocellularity.

Central memory T (TCM) cell

A memory T-cell subpopulation that lacks immediate effector function but that expresses the lymph-node homing molecules L-selectin (CD62L) and CC-chemokine receptor 7 (CCR7). Tcm cells rapidly develop the phenotype and function of effector T cells on antigen re-stimulation in lymphoid organs.

Immunoglobulin class switching

A process in B cells by which the class of a secreted immunoglobulin is changed (for example, from IgM to IgG) without altering its antigen specificity.

Contact hypersensitivity

A form of delayed-type hypersensitivity (type IV), in which T cells respond to antigens that are introduced through skin contact. This step requires dendritic-cell mobilization from the skin to the draining lymph nodes to prime the antigen-specific T cells.

Severe combined immunodeficiency (SCID) mice

Spontaneous mutant mice in which T and B cells are absent. SCID mice lack functional lymphocytes because they have a deficiency that impairs rearrangement of different immunoglobulin and T-cell receptor genes. Lack of T and B cells leads to defects in cell-mediated and humoral immune responses.

Sjögren's syndrome

An autoimmune disorder in which immune cells attack and destroy exocrine glands. The hallmarks of Sjögren's syndrome are dry eyes and dry mouth. The disease is often associated with arthritis.

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Förster, R., Davalos-Misslitz, A. & Rot, A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 8, 362–371 (2008). https://doi.org/10.1038/nri2297

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