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CXC Chemokine Ligand (CXCL) 9 and CXCL10 Are Antagonistic Costimulation Molecules during the Priming of Alloreactive T Cell Effectors

2010; American Association of Immunologists; Volume: 184; Issue: 7 Linguagem: Inglês

10.4049/jimmunol.0903831

1550-6606

Joshua Rosenblum, Naohiko Shimoda, Austin Schenk, Howard Zhang, Danielle D. Kish, Karen S. Keslar, Joshua Μ. Farber, Robert L. Fairchild,

Immunotherapy and Immune Responses

Abstract Donor Ag-reactive CD4 and CD8 T cell production of IFN-γ 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-γ. The absence of CXCL9 in donor allografts, recipients, or both significantly decreased the frequency of donor-reactive CD8 T cells producing IFN-γ and increased the frequency of donor-reactive CD8 T cells producing IL-17A. In contrast, the absence of CXCL10 increased the frequency of IFN-γ–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-γ–producing CD8 T cells, and CXCL10 antagonizes this skewing.