title: Inhibition of CD8+ T cell-derived CD40 signals is necessary but not sufficient for Foxp3+ induced regulatory T cell generation in vivo.
abstract: Current models of CD4(+) T cell help suggest a major role for CD154 binding to CD40 expressed on dendritic cells, with a lesser role for direct T:T interactions via CD40 expressed on CD8(+) T cells. However, the contribution of CD8(+) T cell-derived CD40 signals during the donor-reactive T cell response to a transplant has never been studied. In this study, we examined the graft-rejection kinetics and CD4(+) and CD8(+) donor-reactive T cell responses under conditions in which CD40 was genetically ablated only on APC, as well as under conditions in which CD40 was genetically ablated only on donor-reactive CD8(+) T cells. Our results revealed a significant role for CD8(+) T cell-expressed CD40 in the augmentation of donor-reactive CD8(+) T cell responses following transplantation and showed that CD40 expressed on CD8(+) T cells must be inhibited to allow conversion of CD4(+) T cells into induced regulatory T cells. Thus, this study identifies a major role for CD8(+) T cell-derived CD40 signals as a critical switch factor that both promotes optimal differentiation of cytokine-producing CD8(+) effector T cell responses and inhibits the differentiation of Ag-specific Foxp3(+) induced regulatory T cells in vivo.
authors.affiliation: Department of Surgery, Emory University, Atlanta, GA 30322, USA.
authors.forename: Danya
authors.initials: D
authors.lastname: Liu
authors.forename: Ivana R
authors.initials: IR
authors.lastname: Ferrer
authors.forename: Michael
authors.initials: M
authors.lastname: Konomos
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000032:analysis; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D016038:Skin Transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D019013:CD40 Antigens; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011994:Recombinant Proteins; D023201:CD40 Ligand; D010047:Ovalbumin