title: Emergence of regulatory CD4+ T cell response to repetitive stimulation with antigen-presenting cells in vitro: implications in designing antigen-presenting cell-based tumor vaccines.
abstract: Because APCs play a crucial role in the generation of T cell-mediated immune responses, numerous clinical trials with APC-based vaccines have been initiated in different types of human cancers. Encouraging results have emerged from some of these initial studies. Thus far, APC-based vaccinations usually include multiple rounds of immunization. With this approach, although we and others have detected induction of Ag-specific CTL responses in vaccinated patients after stimulation with the same APC-based immunogen, in vitro we also find that repetitive in vitro stimulation with Ag-loaded APC can, at times, lead to the emergence of noncytolytic CD4+ T cells exhibiting the characteristic phenotype of Th2 cells. These noncytolytic CD4+ T cells synthesize large quantities of type 2 cytokines such as IL-4 and IL-10 on stimulation with the autologous APC or tumor cells in an MHC class II-restricted manner. Further, these CD4+ T cells and a cell-free supernatant factor block the activation of fresh T lymphocytes. The supernatant factor also exhibits a marked inhibitory effect on the expression of the costimulatory molecules, CD80 and CD86, by APC. The inhibitory effect of the supernatant factor can be abrogated by neutralizing IL-10 in the supernatant. These observations therefore have implications in the APC-based tumor vaccine protocol design.
authors.affiliation: Department of Medicine, University of Connecticut School of Medicine, Farmington 06030, USA. chakraborty@sun.uchc.edu
authors.forename: N G
authors.initials: NG
authors.lastname: Chakraborty
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: J R
authors.initials: JR
authors.lastname: Sporn
authors.forename: S H
authors.initials: SH
authors.lastname: Kurtzman
authors.forename: M T
authors.initials: MT
authors.lastname: Ergin
authors.forename: B
authors.initials: B
authors.lastname: Mukherji
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000138:chemical synthesis / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D016219:Immunotherapy, Adoptive / Q000379:methods; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors
chemical_list: D019496:Cancer Vaccines; D007106:Immune Sera; D016753:Interleukin-10