Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model

Hasegawa, Hitoshi; Inoue, Atsushi; Kohno, Masashi; Jin, Lei; Miyazaki, Tatsuhiko; Yoshie, Osamu; Nose, Masato; Yasukawa, Masaki

doi:10.1038/sj.gt.3303051

Cited by 80 publications

(65 citation statements)

References 56 publications

(106 reference statements)

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“…Remarkably, in a murine acute graft-versus-host disease model, transfer of CXCR3-transfected Tregs ameliorated liver disease, due to more pronounced migration and prolonged persistence of highly suppressive CXCR3 + Tregs within the liver (32). These findings correlate very well with our data, because Tregs from Con A-pretreated CXCR3-deficient mice failed to protect against Con A-induced hepatitis in contrast to Tregs from Con A-tolerant wt mice, most probably because of the impaired migration capacity of CXCR3 2/2 Tregs.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Erhardt

Wegscheid

Claass

et al. 2011

The Journal of Immunology

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The chemokine receptor CXCR3 is preferentially expressed by Th1 cells and critically involved in their recruitment to inflamed tissue. In a mouse model of immune-mediated liver injury inducible by Con A, we investigated the role of CXCR3 in acute IFN-γ–mediated hepatitis as well as in tolerance induction, which has been shown to depend on IL-10–producing CD4+CD25+Foxp3+ regulatory T cells (Tregs). Induction of Con A hepatitis resulted in increased intrahepatic expression of the CXCR3 ligands CXCL9, CXCL10, and CXCL11. CXCR3−/− mice developed a more severe liver injury with higher plasma transaminase activities and a more pronounced Th1/Th17 response compared with wild-type (wt) animals upon Con A injection. Moreover, CXCR3−/− mice did not establish tolerance upon Con A restimulation, although Tregs from CXCR3−/− mice were still suppressive in an in vitro suppression assay. Instead, Tregs failed to accumulate in livers of CXCR3−/− mice upon Con A restimulation in contrast to those from wt animals. Con A-tolerant wt mice harbored significantly increased numbers of intrahepatic CXCR3+T-bet+ Tregs that produced IL-10 compared with nontolerant animals. IFN-γ deficiency or anti–IFN-γ Ab treatment demonstrated that conversion to CXCR3+T-bet+ Tregs depended on a Th1 response. Accordingly, in an immunotherapeutic approach, CD4+CD25+Foxp3+ Tregs from Con A-pretreated CXCR3-deficient mice failed to protect against Con A-induced hepatitis, whereas Tregs from Con A-tolerant wt mice allowed CXCR3-deficient mice to recover from Con A hepatitis. In summary, CXCR3+T-bet+IL-10+ Tregs are generated in the liver in dependence of IFN-γ, then disseminated into the organism and specifically migrate into the liver, where they limit immune-mediated liver damage.

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Section: Discussionmentioning

confidence: 99%

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Erhardt

Wegscheid

Claass

et al. 2011

The Journal of Immunology

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“…22,24,28,31 However, to what extent the IFNg-CXCL 9-112CXCR3 cascade contributes to the multi-facetted mechanism of leukocyte recruitment to specific GVHD target organs is not yet completely understood and may further depend on conditioning intensity 18,31 or specific CXCR3 þ T-cell subsets being recruited. 39,65 CXCR6 has been shown to be expressed on liverinfiltrating CD8 þ T cells after allo-BMT and to be functionally involved in the early recruitment of these cells to the liver, but not to the gut. 66,67 Consistent with these findings, in this study, hepatic expression of both CXCR6 and its ligand, CXCL16, was strongly elevated from week 1 to week 3, supporting the concept that the migration of CXCR6 þ T cells to the liver in response to increased ligand expression is operative in aGVHD of the liver.…”

Section: Discussionmentioning

confidence: 99%

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

et al. 2009

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Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT), and infiltration of donor leukocytes into aGVHD target organs is partially orchestrated by chemokines. Using a murine BMT model, the expression of 30 chemokines or chemokine receptors in the lung, liver, gut and tongue was analyzed using real-time PCR at 1, 2, 3 and 6 weeks after BMT during the development of clinical aGVHD and target organ histopathology. CXCL9-11 expression was linked to elevated expression of CXCR3 in the gut, lung and tongue. In contrast, hepatic CXCR3 expression was not changed, whereas a clear association was seen for CXCL16 and CXCR6 expression. An elevated intestinal CCL3 expression 1 week after allo-BMT was associated with an increased expression of CCR5 but not CCR1 or CCR3, and in the lung and liver CCL3-CCL5 expression was associated with increases in CCR1 and CCR5. Overexpression of CCL2, CCL8, CCL12 and their receptor CCR2 was found in the liver and lung, but not in the gut and tongue. On the basis of the differences in kinetics and organ distribution, more studies are required to better characterize specific targets within this network, as this will allow the development of novel preventive and therapeutic approaches by using single or multiple targeting reagents.

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“…For example, in ConAinduced Th1-driven hepatitis, CXCR3-deficient Treg failed to migrate towards CXCR3 ligands CXCL9, CXCL10 and CXCL11, which are highly expressed in the inflammatory liver, resulting in massive liver damage by unregulated Th1 effectors [19]. In a reciprocal study, forced expression of CXCR3 on Tregs increased their ability to decrease hepatic and gut acute graft-versus-host disease (GVHD) in a murine model of experimental GVHD [21]. Importantly, CXCR3-deficient Tregs are efficient at suppressing Th1 cells in vitro [19], again supporting the contention that the primary role of T-bet expression in Tregs is to modify homing and allow them to colocalise with Th1 cells (Fig.…”

Section: Foxp3mentioning

confidence: 99%

Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

2012

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The potential for self‐reactive T cells to cause autoimmune disease is held in check by Foxp3+ regulatory T cells (Tregs), essential mediators of peripheral immunological tolerance. Tregs have the capacity to suppress multiple branches of the immune system, tightly controlling the different subsets of effector T cells across multiple different tissue environments. Recent genetic experiments have found mutations that disrupt specific Treg: effector T cell relationships, leading to the possibility that subsets of Tregs are required to suppress each subset of effector T cells. Here we review the environmental factors and mechanisms that allow Tregs to suppress specific subsets of effector T cells, and find that a parsimonious explanation of the genetic data can be made without invoking Treg subsets. Instead, Tregs show a functional and chemotactic plasticity based on microenvironmental influences that allows the common pool of cells to suppress multiple distinct immune responses.

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Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model

Cited by 80 publications

References 56 publications

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

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