The chemokine receptor CCR7 controls lymph node-dependent cytotoxic T cell priming in alloimmune responses.
The chemokine receptor CCR7 and its ligands regulate migration and colocalization of T cells and mature dendritic cells to and within secondary lymphoid organs. The requirement of CCR7 in efficient priming of allospecific cytotoxic CD8(+) T cells is poorly characterized. Here, we demonstrate a role for CCR7 in the initiation of an alloimmune response and in the development of transplant rejection. Remarkably, in a model of acute allogeneic tumor rejection, CCR7(-/-) mice completely failed to reject subcutaneously injected MHC class I mismatched tumor cells and cytotoxic activity of allospecific T cells was severely compromised. When solid tumors derived from wild-type mice were transplanted, recipient CCR7(-/-) mice were capable of rejecting the allografts. In contrast, tumor allografts transplanted from CCR7(-/-) donors onto CCR7(-/-) recipients showed allograft survival up to 28 days, suggesting a critical function of CCR7 on donor-type passenger leukocytes in the initiation of cytotoxic CD8(+) T cell responses. In a heterotopic heart transplantation model CCR7 deficiency resulted in significantly prolonged but not indefinite allograft survival. Additional prolongation of graft survival was observed when hearts from CCR7(-/-) mice were used as donor organs. Our results define a key role for CCR7 in allogeneic T cell priming within the context of draining lymph nodes.
Höpken
Uta E
UE
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany. uhoepken@mdc-berlin.de
Droese
Jana
J
Li
Jian-Ping
JP
Joergensen
Joanne
J
Breitfeld
Dagmar
D
Zerwes
Hans-Günter
HG
Lipp
Martin
M
D019264:Adoptive Transfer; D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology*; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000912:Antibodies, Neoplasm; C515371:Ccr7 protein, mouse; D015395:Histocompatibility Antigens Class I; D054400:Receptors, CCR7; D019707:Receptors, Chemokine