title: Inhibiting CXCR3-dependent CD8+ T cell trafficking enhances tolerance induction in a mouse model of lung rejection.
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.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Seung
authors.forename: Josalyn L
authors.initials: JL
authors.lastname: Cho
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Medoff
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology*; D051379:Mice; D054367:Receptors, CXCR3 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3