CCR7 Signaling Inhibits T Cell Proliferation

Ziegler, Ekkehard; Oberbarnscheidt, Martin H.; Bulfone–Paus∥, Silvia; Förster, Reinhold; Kunzendorf, Ulrich; Krautwald, Stefan

doi:10.4049/jimmunol.179.10.6485

Cited by 43 publications

(33 citation statements)

References 50 publications

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“…Although our results have not identified the exact chemokine or combination of chemokines responsible for recruiting and retaining iTregs in the gastric mucosa, we have identified several candidates (CCL3, CCL4, CCL20, CCL9, CXCL10, and XCL1) that are likely to be important during this process. These chemokines may also be involved in the suppressor activity of iTregs, as others have reported that chemokines such as XCL1, CCL4, and CCR7 ligands can have immunosuppressive effects on effector T cells (54,56,57). A preliminary examination of chemokine receptor expression revealed that the effector T cells and iTregs described in these studies expressed similar levels of CCR1 and CCR3 and that effector T cells express higher levels of CCR5 (data not shown).…”

Section: Discussionmentioning

confidence: 50%

Antigen-Specific TGF-β–Induced Regulatory T Cells Secrete Chemokines, Regulate T Cell Trafficking, and Suppress Ongoing Autoimmunity

Nguyen

Sullivan

Ebel

et al. 2011

The Journal of Immunology

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The ability to regulate ongoing inflammation using regulatory T cells (Tregs) is under intense investigation. Strategies to induce and expand Ag-specific Tregs are being developed, and whether various types of Tregs are suppressive in the inflammatory conditions associated with ongoing disease needs to be determined. In this study, we report that TGF-β–induced Tregs (iTregs) and expanded Tregs specific for a major self-Ag in autoimmune gastritis suppress inflammation and associated pathology when administered late in the process of ongoing disease. Transferred iTregs localized to the stomach, maintained Foxp3 and suppressor functions, and engaged several distinct mechanisms to alleviate disease progression. In addition to suppressing the production of inflammatory cytokines in the stomach and preventing the destruction of parietal cells, we show that iTregs secrete numerous chemokines and regulate both iTreg and effector T cell trafficking into the stomach. These data support efforts to use iTregs in therapies to treat autoimmunity and inflammatory diseases and provide novel insight into the biological mechanisms of iTreg-mediated immune suppression.

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Section: Discussionmentioning

confidence: 50%

Antigen-Specific TGF-β–Induced Regulatory T Cells Secrete Chemokines, Regulate T Cell Trafficking, and Suppress Ongoing Autoimmunity

Nguyen

Sullivan

Ebel

et al. 2011

The Journal of Immunology

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“…H17 stimulation also induces CCL19 production in tumor cells, and the released CCL19 recruits and expands pluripotent and immunoregulatory CD271 Connections between CCL19 and immune dysfunction have been recently demonstrated. CCL19 directly impairs T cells by suppressing cell proliferation and IL-2 production through CCR7 signaling (29), or by promoting activation-induced cell death (30). As an indirect action, CCL19 recruits immunosuppressive CCR7 þ…”

Section: Discussionmentioning

confidence: 99%

Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

et al. 2014

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Human endogenous retroviruses (HERV) are associated with many diseases such as autoimmune diseases and cancer. Although the frequent expression of a variety of HERVs in tumor cells has been demonstrated, their functional contributions in cancer are as yet unclear. Intriguingly, HERVs and other retroviruses include an immunosuppressive domain in their transmembrane envelope proteins, but its mechanism of action and cancer relevance are obscure. In this study, we demonstrate that the human endogenous retrovirus HERV-H has a critical role in tumor metastasis and immune escape. We found that expression of herv-h mRNA was elevated in metastatic tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and in primary tumor tissues from advanced colon cancer. The immunosuppressive peptide H17 derived from HERV-H was sufficient to induce EMT in tumor cells that expressed low levels of HERV-H, and it amplified this event within the tumor microenvironment. H17 also stimulated CCL19 expression in tumor cells, which in turn recruited and expanded a population of pluripotent immunoregulatory CD271 þ cells, which included mesenchymal stem cells and myeloid-derived suppressor cells. In tumor tissues from patients with advanced colon cancer, we confirmed that CD271 þ cells were increased in HERV-H þ CCL19 þ tumor tissues. Notably, RNAi-mediated change of HERV-H or CCL19, or depletion of CD271 þ cells, improved immune responses in vitro and in vivo accompanied by tumor regression. Together, our results argued that HERV-H is a critical determinant of immune escape in cancer, suggesting its candidacy as a promising therapeutic target to treat patients with advanced cancer.

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“…During this exposure, if a large number of CCR7 receptors were internalized, this could prevent the cell from reaching the CCL19 expressing dendritic cells. Recently, systemic application of CCL19-Ig, which likely internalized most available CCR7, prevented T cells from forming conjugates with dendritic cells in the lymph nodes, in vivo (68). In addition, whereas in the presence of a CCL19 antagonist cells were able to migrate to the lymph nodes, they failed to exit (69).…”

Section: Discussionmentioning

confidence: 99%

Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21

Byers

Calloway

Shannon

et al. 2008

The Journal of Immunology

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Internalization of ligand bound G protein-coupled receptors, an important cellular function that mediates receptor desensitization, takes place via distinct pathways, which are often unique for each receptor. The C-C chemokine receptor (CCR7) G protein-coupled receptor is expressed on naive T cells, dendritic cells, and NK cells and has two endogenous ligands, CCL19 and CCL21. Following binding of CCL21, 21 ± 4% of CCR7 is internalized in the HuT 78 human T cell lymphoma line, while 76 ± 8% of CCR7 is internalized upon binding to CCL19. To determine whether arrestins mediated differential internalization of CCR7/CCL19 vs CCR7/CCL21, we used small interfering RNA (siRNA) to knock down expression of arrestin 2 or arrestin 3 in HuT 78 cells. Independent of arrestin 2 or arrestin 3 expression, CCR7/CCL21 internalized. In contrast, following depletion of arrestin 3, CCR7/CCL19 failed to internalize. To examine the consequence of complete loss of both arrestin 2 and arrestin 3 on CCL19/CCR7 internalization, we examined CCR7 internalization in arrestin 2−/−/arrestin 3−/− murine embryonic fibroblasts. Only reconstitution with arrestin 3-GFP but not arrestin 2-GFP rescued internalization of CCR7/CCL19. Loss of arrestin 2 or arrestin 3 blocked migration to CCL19 but had no effect on migration to CCL21. Using immunofluorescence microscopy, we found that arrestins do not cluster at the membrane with CCR7 following ligand binding but cap with CCR7 during receptor internalization. These are the first studies that define a role for arrestin 3 in the internalization of a chemokine receptor following binding of one but not both endogenous ligands.

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CCR7 Signaling Inhibits T Cell Proliferation

Cited by 43 publications

References 50 publications

Antigen-Specific TGF-β–Induced Regulatory T Cells Secrete Chemokines, Regulate T Cell Trafficking, and Suppress Ongoing Autoimmunity

Antigen-Specific TGF-β–Induced Regulatory T Cells Secrete Chemokines, Regulate T Cell Trafficking, and Suppress Ongoing Autoimmunity

Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21

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