Inhibiting CXCR3-Dependent CD8+ T Cell Trafficking Enhances Tolerance Induction in a Mouse Model of Lung Rejection

Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
The Journal of Immunology (Impact Factor: 5.52). 06/2011; DOI: 10.4049/jimmunol.1001049
Source: PubMed

ABSTRACT Lung transplantation remains the only effective therapy for patients with end-stage pulmonary diseases. Unfortunately, acute rejection of the lung remains a frequent complication and is an important cause of morbidity and mortality. The induction of transplant tolerance is thought to be dependent, in part, on the balance between allograft effector mechanisms mediated by effector T lymphocytes (Teff), and regulatory mechanisms mediated by FOXP3(+) regulatory T cells (Treg). In this study, we explored an approach to tip the balance in favor of regulatory mechanisms by modulating chemokine activity. We demonstrate in an adoptive transfer model of lung rejection that CXCR3-deficient CD8(+) Teff have impaired migration into the lungs compared with wild-type Teff, which results in a dramatic reduction in fatal pulmonary inflammation. The lungs of surviving mice contained tolerized CXCR3-deficient Teff, as well as a large increase in Treg. We confirmed that Treg were needed for tolerance and that their ability to induce tolerance was dependent on their numbers in the lung relative to the numbers of Teff. These data suggest that transplantation tolerance can be achieved by reducing the recruitment of some, but not necessarily all, CD8(+) Teff into the target organ and suggest a novel approach to achieve transplant tolerance.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Chemokine (C-X-C motif) receptor 3 (CXCR3) is a chemokine receptor involved in the regulation of immune cell trafficking and activation. We observed increased CXCR3 expression in the visceral adipose of obese humans and mice. We hypothesized a pathophysiologic role for CXCR3 in diet-induced obesity (DIO). Design and Methods: Wild type C57B/L6J (WT) and chemokine receptor 3 knockout (CXCR3(-/-) ) mice were fed a high fat diet (HFD) for 20 weeks followed by assessment of glucose metabolism and VAT inflammation. Results: CXCR3(-/-) mice exhibited lower fasting glucose and improved glucose tolerance compared to WT-HFD mice, despite similar body mass. HFD-induced VAT innate and adaptive immune cell infiltration, including immature myeloid cells (CD11b(+) F4/80(lo) Ly6C(+) ), was markedly ameliorated in CXCR3(-/-) mice. In vitro IBIDI and in vivo migration assays demonstrated no CXCR3-mediated effect on macrophage or monocyte migration, respectively. CXCR3(-/-) macrophages, however, had a blunted response to interferon-γ, a TH 1 cytokine that induces macrophage activation. Conclusions: We demonstrate a previously unreported role for CXCR3 in the development of HFD-induced insulin resistance and VAT macrophage infiltration in mice. Our results support pharmaceutical targeting of the CXCR3 receptor as a potential treatment for obesity/insulin resistance.
    Obesity 10/2013; · 3.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8(+) T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8(+) T cell-mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA)-specific cytotoxic T lymphocytes (CTL) induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice). The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA.RAG(-/-) mice, we found that CD4(+) T cells and ICOS(+/+) T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4(+)Foxp3 (+) ICOS(+) T cells were enriched in the lungs of animals surviving lung injury and ICOS(+/+) Tregs promoted survival in animals that received ICOS(-/-) T cells. Direct comparison of ICOS(-/-) Tregs to ICOS(+/+) Tregs found defects in vitro but no differences in the ability of ICOS(-/-) Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function.
    PLoS ONE 01/2013; 8(8):e72955. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. It is increasingly evident that the gestational uterine microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the maternal-fetal interface and regulate multiple events that are closely associated with normal pregnancy. Here, we review the expression and function of chemokines and their receptors at the maternal-fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells so as to form a fetus-supporting milieu during pregnancy. The chemokine network is also involved in pregnancy complications.Cellular & Molecular Immunology advance online publication, 11 August 2014; doi:10.1038/cmi.2014.68.
    Cellular & molecular immunology. 08/2014;

Full-text (2 Sources)

Available from
May 21, 2014