title: CCR4 dependent migration of Foxp3+ Treg cells to skin grafts and draining lymph nodes is implicated in enhanced graft survival in CD200tg recipients.
abstract: We have previously reported that transgenic overexpression of CD200 in either mouse skin graft donors or recipients significantly enhances skin allograft survival. By focused microarray analysis we showed this enhanced graft survival is associated with increased expression of Foxp3, GITR, CTLA-4 and CCR4 mRNA, all genes related to T(reg) cell induction/function, and of Gata3, IL-4, IL-5, IL-13, and somewhat surprisingly, of T-bet, INF-γ and granzyme b. Gene-specific real-time PCR and immunohistochemistry analysis confirmed an increase in Foxp3(+) T(reg) cells in both the skin grafts and draining lymph nodes (DLNs) of CD200(tg) recipient mice at both 7/14 days post engraftment, as well as providing evidence for increased expression of the ligands for CCR4, CCL17 and CCL22 in both locations. Following lentivirus-mediated shRNA treatment of Dox-treated CD200(tg) mice to attenuate expression of CCR4 mRNA, the increased localization of T(reg) cells in skin/DLN of CD200(tg) recipients was abolished, and the enhanced graft survival similarly reversed. We conclude that enhanced CCR4 dependent migration of Foxp3(+) T(reg) to grafted tissue and DLNs is an essential step in the graft prolongation afforded by overexpression of CD200.
authors.affiliation: Transplant Research Division, University Health Network, Toronto, ON, Canada.
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Zhiqi
authors.initials: Z
authors.lastname: Chen
authors.forename: Ismat
authors.initials: I
authors.lastname: Khatri
authors.forename: Reginald M
authors.initials: RM
authors.lastname: Gorczynski
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D054414:Chemokine CCL17 / Q000276:immunology / Q000378:metabolism; D054422:Chemokine CCL22 / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D006085:Graft Survival / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D054398:Receptors, CCR4 / Q000276:immunology / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; C515482:CCL22 protein, human; C492346:CD200 receptor, mouse; C499538:Ccl17 protein, mouse; C515355:Ccr4 protein, mouse; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D018793:Interleukin-13; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D054398:Receptors, CCR4; D015847:Interleukin-4; C042739:antigens, CD200