title: Graft-versus-host disease impairs vaccine responses through decreased CD4+ and CD8+ T cell proliferation and increased perforin-mediated CD8+ T cell apoptosis.
abstract: Tumor-targeted vaccines represent a strategy to enhance the graft-versus-leukemia effect after allogeneic blood and marrow transplantation (BMT). We have previously shown that graft-versus-host disease (GVHD) can negatively impact quantitative responses to vaccines. Using a minor histocompatibility Ag-mismatched BMT (B6 → B6 × C3H.SW) followed by adoptive transfer of HY-specific T cells and HY-expressing dendritic cells, we assessed whether GVHD induced by donor lymphocyte infusion (DLI) affects the persistence, proliferation, and survival of vaccine-responding, nonalloantigen reactive T cells. Both CD8(+) and CD4(+) HY-specific T cells undergo less vaccine-driven proliferation in allogeneic recipients with GVHD. Although vaccine-responding CD8(+) T cells show decreased IFN-γ and CD107a production, CD4(+) T cells exhibit increased programmed death 1 and T cell Ig mucin-like domain 3 expression. In addition, the degree of apoptosis in vaccine-responding CD8(+) T cells was higher in the presence of GVHD, but there was no difference in CD4(+) T cell apoptosis. Using Fas ligand-deficient or TRAIL-deficient DLI had no impact on apoptosis of HY-specific T cells. However, perforin-deficient alloreactive DLI induced significantly less apoptosis of vaccine-responding CD8(+) T cells and resulted in enhanced tumor protection. Thus, diminished vaccine responses during GVHD result from impaired proliferation of CD8(+) and CD4(+) T cells responding to vaccination, with an additional contribution from perforin-mediated CD8(+) T cell apoptosis. These results provide important insights toward optimizing vaccine responses after allogeneic BMT.
authors.affiliation: Blood and Marrow Transplant Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ccapitini@pediatrics.wisc.edu
authors.forename: Christian M
authors.initials: CM
authors.lastname: Capitini
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Nasholm
authors.forename: Brynn B
authors.initials: BB
authors.lastname: Duncan
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D020296:Animals, Congenic; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy; D002455:Cell Division; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D053222:Fas Ligand Protein / Q000172:deficiency / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D006182:H-Y Antigen / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology; D007167:Immunotherapy; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D052899:Pore Forming Cytotoxic Proteins / Q000502:physiology*; D011828:Radiation Chimera; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000276:immunology; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006182:H-Y Antigen; D016056:Immunodominant Epitopes; D015778:Minor Histocompatibility Antigens; D052899:Pore Forming Cytotoxic Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; C483886:perforin, mouse