title: Role of alpha 5 beta 1 integrin in TGF-beta 1-costimulated CD8+ T cell growth and apoptosis.
abstract: TGF-beta 1 regulates cell growth, differentiation, and adhesion and is a potent immunosuppressant, in part through its well-recognized growth-inhibitory effects. However, certain T cell subsets, particularly of naive phenotype, can instead be costimulated to proliferate by TGF-beta 1. We have previously demonstrated that naive murine CD8+ T cells, TCR activated by platebound anti-CD3 Ab or SEB superantigen, are growth stimulated by TGF-beta 1, acquire a memory phenotype, express elevated IL-10 and TGF-beta 1, and cause T cell growth inhibition as effector CD8+ T cells. TGF-beta 1 causes growth among certain nonlymphoid cells in part by inducing or mimicking integrin activation. The present studies thus addressed mediation of TGF-beta 1-dependent growth and survival of anti-CD3-triggered CD8+ T cells via beta 1 integrins. TGF-beta 1 reduced anti-CD3-activated alpha 4 beta 1 integrin expression and constitutive adhesion to fibronectin, while initial alpha 5 beta 1 expression was heightened and adhesive function sustained. Fibronectin-based RGD peptides that bind alpha 5 beta 1 integrins and alpha 5 or beta 1 integrin chain-specific Abs blocked TGF-beta 1-dependent proliferation, while connecting segment-1 peptide that binds alpha 4 beta 1 integrin and alpha 4 chain-specific Abs had no effect. Cross-linked alpha 5- but not alpha 4-specific Ab mimicked TGF-beta 1 function by costimulating CD8+ T cell growth. TGF-beta 1 also caused RGD peptide-sensitive CD8+ T cell aggregation. Additionally, TGF-beta 1-costimulated proliferation correlated with TGF-beta 1 protection of CD8+ T cells from anti-CD3-induced apoptosis. RGD peptides and alpha 5 integrin-specific Ab abolished TGF-beta 1 prevention of activation-induced apoptosis. Therefore, TGF-beta 1 costimulates CD8+ T cell growth via activation of the alpha 5 beta 1 integrin and/or its ligand and supports sustained growth at least in part by alpha 5 beta 1-mediated protection from activation-induced apoptosis.
authors.affiliation: Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rich
authors.forename: N
authors.initials: N
authors.lastname: Van Nood
authors.forename: H M
authors.initials: HM
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D004253:DNA Nucleotidylexotransferase / Q000032:analysis; D005353:Fibronectins / Q000502:physiology; D016130:Immunophenotyping; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000502:physiology; D017469:Receptors, Fibronectin / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*
chemical_list: D005353:Fibronectins; D016023:Integrins; D009842:Oligopeptides; D017469:Receptors, Fibronectin; D016212:Transforming Growth Factor beta; C047981:arginyl-glycyl-aspartic acid; D004253:DNA Nucleotidylexotransferase