title: Co-stimulation with 4-1BB ligand allows extended T-cell proliferation, synergizes with CD80/CD86 and can reactivate anergic T cells.
abstract: Activation of T cells requires co-stimulation, in addition to signals through the antigen-receptor complex. Antigen encounter without adequate co-stimulation results in T-cell desensitization or anergy, a mechanism of peripheral tolerance and an apparent obstacle to cancer immunotherapy. One important co-stimulatory pathway involves CD28 engagement by CD80 or CD86. However, other ligand-receptor pairs can also provide co-stimulation and may have important functions modulating the immune response. Previous reports indicated that co-stimulation using 4-1BB ligand (4-1BBL) or agonistic anti-4-1BB antibodies could prolong T-cell responses, avoid activation-induced cell death and promote anti-tumour responses in mice. To further investigate the potential for cancer immunotherapy, we studied the effects of CD80/CD86 and 4-1BBL in repeated stimulation of human T cells and asked whether 4-1BBL might be capable of reversing anergy. We expressed CD80, CD86 and 4-1BBL in A549 lung carcinoma cells using adenovirus vectors and co-cultured these with human T cells stimulated with anti-CD3 antibody. Proliferation co-stimulated by CD80 or CD86 was transient; however, 4-1BBL-co-stimulated cultures continued to proliferate for up to 5 weeks, with repeated stimulation. Combined co-stimulation with CD80/CD86 and 4-1BBL also allowed continuous proliferation at a faster rate than either signal alone. Co-stimulation with 4-1BBL did not suppress expression of the inducible, inhibitory CD80/CD86R, CTLA-4. Significantly, we show that T cells that had become non-responsive to anti-CD3, either alone or together with CD80/CD86 co-stimulation, and thus were anergic, could be reactivated to proliferate when costimulated with 4-1BBL, either alone or combined with CD80/CD86.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Habib-Agahi
authors.forename: Thanh T
authors.initials: TT
authors.lastname: Phan
authors.forename: Peter F
authors.initials: PF
authors.lastname: Searle
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse