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The Role of Chemokines in Shaping the Balance Between CD4(+) T Cell Subsets and Its Therapeutic Implications in Autoimmune and Cancer Diseases.

Karin N, Wildbaum G - Front Immunol (2015)

Bottom Line: Many studies, including ours, imply that targeting the function of several key chemokines, but not many others, could effectively suppress inflammatory responses and inflammatory autoimmunity.First, we elaborate the role of cytokines in directing the polarization of effector and regulatory T cell subset and the plasticity of this process.Finally, we elaborate the potential clinical implications of these studies for therapy of autoimmunity, graft-versus-host disease, and cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Rappaport Family Institute for Research in the Medical Sciences Rappaport Faculty of Medicine, Technion - Israel Institute of Technology , Haifa , Israel.

ABSTRACT
Chemokines are the key activators of adhesion molecule and also drivers of leukocyte migration to inflammatory sites and are therefore mostly considered as proinflammatory mediators. Many studies, including ours, imply that targeting the function of several key chemokines, but not many others, could effectively suppress inflammatory responses and inflammatory autoimmunity. Along with this, a single chemokine named CXCL10 could be used to induce antitumor immunity, and thereby suppress myeloma. Our working hypothesis is that some chemokines differ from others as aside from being chemoattractants for leukocytes and effective activators of adhesion receptors that possess additional biological properties making them "driver chemokines." We came up with this notion when studying the interlay between CXCR4 and CXCL12 and between CXCR3 and its three ligands: CXCL9, CXCL10, and CXCL11. The current mini-review focuses on these ligands and their biological properties. First, we elaborate the role of cytokines in directing the polarization of effector and regulatory T cell subset and the plasticity of this process. Then, we extend this notion to chemokines while focusing on CXCL 12 and the CXCR3 ligands. Finally, we elaborate the potential clinical implications of these studies for therapy of autoimmunity, graft-versus-host disease, and cancer.

No MeSH data available.


Related in: MedlinePlus

The role of CXC chemokines in driving the polarization and biological function of CD4+ T cell subsets.
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Figure 1: The role of CXC chemokines in driving the polarization and biological function of CD4+ T cell subsets.

Mentions: We have investigated the interplay between CXCR3 and its three ligands: CXCL9, CXCL10, and CXCL11 on directing the polarization of CD4+ T cells. We observed that while CXCL9 and CXCL10 skew T cell polarization into Th1/Th17 effector cells, CXCL11 drives CD4+ T cell polarization into IL-10-producing Tr-1 (11). We also uncovered the signaling basis of this biased response, and learned that it is GαI independent (11). While CXCL10/CXCR3 interactions drive effector Th1 polarization via STAT1, STAT4, and STAT5 phosphorylation, CXCL11/CXCR3 binding induces an immunotolerizing state that is characterized by IL-10high (Tr1) and IL-4high (Th2) cells and mediated via p70 kinase/mTOR in STAT-3- and STAT-6-dependent pathways (11). CXCL11 binds CXCR3 a higher affinity than CXCL10, suggesting that CXCL11 has potential to mediate and restrain inflammatory autoimmunity (Figure 1). This may explain, in part, why CXCR3-deficient mice develop an extremely severe form of EAE and T1DM (66, 67).


The Role of Chemokines in Shaping the Balance Between CD4(+) T Cell Subsets and Its Therapeutic Implications in Autoimmune and Cancer Diseases.

Karin N, Wildbaum G - Front Immunol (2015)

The role of CXC chemokines in driving the polarization and biological function of CD4+ T cell subsets.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663243&req=5

Figure 1: The role of CXC chemokines in driving the polarization and biological function of CD4+ T cell subsets.
Mentions: We have investigated the interplay between CXCR3 and its three ligands: CXCL9, CXCL10, and CXCL11 on directing the polarization of CD4+ T cells. We observed that while CXCL9 and CXCL10 skew T cell polarization into Th1/Th17 effector cells, CXCL11 drives CD4+ T cell polarization into IL-10-producing Tr-1 (11). We also uncovered the signaling basis of this biased response, and learned that it is GαI independent (11). While CXCL10/CXCR3 interactions drive effector Th1 polarization via STAT1, STAT4, and STAT5 phosphorylation, CXCL11/CXCR3 binding induces an immunotolerizing state that is characterized by IL-10high (Tr1) and IL-4high (Th2) cells and mediated via p70 kinase/mTOR in STAT-3- and STAT-6-dependent pathways (11). CXCL11 binds CXCR3 a higher affinity than CXCL10, suggesting that CXCL11 has potential to mediate and restrain inflammatory autoimmunity (Figure 1). This may explain, in part, why CXCR3-deficient mice develop an extremely severe form of EAE and T1DM (66, 67).

Bottom Line: Many studies, including ours, imply that targeting the function of several key chemokines, but not many others, could effectively suppress inflammatory responses and inflammatory autoimmunity.First, we elaborate the role of cytokines in directing the polarization of effector and regulatory T cell subset and the plasticity of this process.Finally, we elaborate the potential clinical implications of these studies for therapy of autoimmunity, graft-versus-host disease, and cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Rappaport Family Institute for Research in the Medical Sciences Rappaport Faculty of Medicine, Technion - Israel Institute of Technology , Haifa , Israel.

ABSTRACT
Chemokines are the key activators of adhesion molecule and also drivers of leukocyte migration to inflammatory sites and are therefore mostly considered as proinflammatory mediators. Many studies, including ours, imply that targeting the function of several key chemokines, but not many others, could effectively suppress inflammatory responses and inflammatory autoimmunity. Along with this, a single chemokine named CXCL10 could be used to induce antitumor immunity, and thereby suppress myeloma. Our working hypothesis is that some chemokines differ from others as aside from being chemoattractants for leukocytes and effective activators of adhesion receptors that possess additional biological properties making them "driver chemokines." We came up with this notion when studying the interlay between CXCR4 and CXCL12 and between CXCR3 and its three ligands: CXCL9, CXCL10, and CXCL11. The current mini-review focuses on these ligands and their biological properties. First, we elaborate the role of cytokines in directing the polarization of effector and regulatory T cell subset and the plasticity of this process. Then, we extend this notion to chemokines while focusing on CXCL 12 and the CXCR3 ligands. Finally, we elaborate the potential clinical implications of these studies for therapy of autoimmunity, graft-versus-host disease, and cancer.

No MeSH data available.


Related in: MedlinePlus