title: Costimulatory strength influences the differential effects of transforming growth factor beta1 for the generation of CD8+ regulatory T cells.
abstract: Transforming growth factor beta1 (TGFbeta1) is a pleiotropic cytokine, capable of exerting diverse biologic effects. Despite its central role in multiple immune activities, the molecular signals responsible for shaping TGFbeta1's immunologic properties remain poorly elucidated. We report that costimulatory strength acts as a molecular switch, which influences the differential effects of TGFbeta1 on the effector and regulatory development of naïve CD8+ lymphocytes. At low costimulation, TGFbeta1 inhibits proliferation of CD8+ lymphocytes and cytokine secretion, but at high costimulation the response to TGFbeta1 is quite different. High costimulation combined with TGFbeta1 generates CD8+CD25+ T lymphocytes which maintain robust proliferative and survival capacity in the presence of low IL-2 concentrations. Furthermore, under these conditions, a subpopulation of CD8+ T lymphocytes is generated that express Foxp3, secrete IL-10, and inhibit naïve T lymphocyte proliferation via a contact-dependent mechanism. The adoptive transfer of these CD8+CD25+Foxp3+ T cells into mice inoculated intravenously with B16F10 melanoma appears to accelerate tumor progression as reflected by an increase in the number of pulmonary metastatic tumor foci. These findings indicate that costimulatory strength may act as a molecular switch in the generation of CD8+ T cells which possess a regulatory phenotype and the capacity to reduce antitumor immune responses within tumor-bearing mice.
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, 1008 West Hazelwood Drive, Urbana, IL 61801, USA. t-fan@uiuc.edu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Roy
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000276:immunology; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D007371:Interferon-gamma