title: CXC chemokine ligand (CXCL) 9 and CXCL10 are antagonistic costimulation molecules during the priming of alloreactive T cell effectors.
abstract: Donor Ag-reactive CD4 and CD8 T cell production of IFN-gamma is a principal effector mechanism promoting tissue injury during allograft rejection. The CXCR3-binding chemokines CXCL9 and CXCL10 recruit donor-reactive T cells to the allograft, but their role during the priming of donor-reactive T cells to effector function is unknown. Using a murine model of MHC-mismatched cardiac transplantation, we investigated the influence of CXCL9 and CXCL10 during donor-reactive T cell priming. In allograft recipient spleens, CXCL9 and CXCL10 were expressed as early as 24 h posttransplant and increased with similar kinetics, concurrently with CXCR3 expression on T cells. CXCL9, but not CXCL10, expression required NK cell production of IFN-gamma. The absence of CXCL9 in donor allografts, recipients, or both significantly decreased the frequency of donor-reactive CD8 T cells producing IFN-gamma and increased the frequency of donor-reactive CD8 T cells producing IL-17A. In contrast, the absence of CXCL10 increased the frequency of IFN-gamma-producing CD8 T cells in a CXCL9-dependent manner. These data provide novel evidence that donor-reactive CD8 T cells use the CXCR3 chemokine axis as a costimulation pathway during priming to allografts where CXCL9 promotes the development of IFN-gamma-producing CD8 T cells, and CXCL10 antagonizes this skewing.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. jmr55@case.edu
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Rosenblum
authors.forename: Naohiko
authors.initials: N
authors.lastname: Shimoda
authors.forename: Austin D
authors.initials: AD
authors.lastname: Schenk
authors.forename: Howard
authors.initials: H
authors.lastname: Zhang
authors.forename: Danielle D
authors.initials: DD
authors.lastname: Kish
authors.forename: Karen
authors.initials: K
authors.lastname: Keslar
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Farber
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fairchild
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D054357:Chemokine CXCL10 / Q000276:immunology* / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D007371:Interferon-gamma