title: CD3/CD28-costimulated T1 and T2 subsets: differential in vivo allosensitization generates distinct GVT and GVHD effects.
abstract: Adoptive T-cell therapy using CD3/CD28 co-stimulation likely requires in vivo generation of antigen specificity. Because CD28 promotes TH1/TC1 (T1) or TH2/TC2 (T2) differentiation, costimulation may generate donor T1 or T2 cells capable of differentially mediating allogeneic graft-versus-tumor (GVT) effects and graft-versus-host disease (GVHD). Costimulation under T1 or T2 conditions indeed generated murine TH1/TC1 cells secreting interleukin-2/interferon-gamma (IL-2/IFN-gamma) or TH2/TC2 cells secreting IL-4/IL-5/IL-10. In vivo, allogeneic T1 cells expanded, maintained T1 secretion, and acquired allospecificity involving IFN-gamma and IL-5. In contrast, allogeneic T2 cells expanded less and maintained T2 secretion but did not develop significant allospecificity.Allogeneic, but not syngeneic, T1 cells mediated a GVT effect against host-type breast cancer cells, as median survival time (MST) increased from 25.6 +/- 2.6 (tumor controls) to 69.2 +/- 5.9 days (P < 1.2 x 10(-9)). This T1-associated GVT effect operated independently of fasL because T1 cells from gld mice mediated tumor-free survival. In contrast, allogeneic T2 cells mediated a modest, noncurative GVT effect (MST, 29 +/- 1.3 days; P <.0019). T1 recipients had moderate GVHD (histologic score, 4 of 12) that contributed to lethality after bone marrow transplantation; in contrast, T2 recipients had minimal GVHD (histologic score, 1 of 12). CD3/CD28 co-stimulation, therefore, generates T1 or T2 populations with differential in vivo capacity for expansion to alloantigen, resulting in differential GVT effects and GVHD.
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20892, USA. jungu@mail.nih.gov
authors.forename: Unsu
authors.initials: U
authors.lastname: Jung
authors.forename: Jason E
authors.initials: JE
authors.lastname: Foley
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Erdmann
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eckhaus
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000502:physiology*; D017252:CD3 Complex / Q000502:physiology*; D045744:Cell Line, Tumor; D006086:Graft vs Host Disease; D020350:Graft vs Tumor Effect; D007111:Immunity, Cellular; D007114:Immunization; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D051379:Mice; D008815:Mice, Inbred Strains; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D007378:Interleukins; D007371:Interferon-gamma