title: Role of CD80, CD86, and CTLA4 on mouse CD4(+) T lymphocytes in enhancing cell-cycle progression and survival after activation with PMA and ionomycin.
abstract: Cell surface interactions between the T cell costimulatory receptors, CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA4), with their cognate ligands, CD80 and CD86, on antigen-presenting cells play an important role in T cell activation. Although CD80 and CD86 are induced on T cells after activation, not much is known about their role in modulating T cell function. We show that CD80, CD86, and CTLA4 are induced on purified CD4(+) T cells after in vitro activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and they play an essential role for proliferation and survival. Blockade of CTLA4-CD80/CD86 interactions greatly reduces PMA and ionomycin-mediated mouse CD4(+) T cell activation. The three key features of this inhibition of activation are: First, late events in T cell activation (after 18 h) are affected; second, these cells do not undergo anergy; and third, CD4(+)CD25(+) regulatory T cells are not responsible. Activation of T cells with PMA and ionomycin together with CTLA4-CD80/CD86 blockade results in decreased induction of CD25 and Bcl-X(L), reduced interleukin (IL)-2, and enhanced transforming growth factor-beta (TGF-beta) production. Furthermore, extended CTLA4-CD80/CD86 blockade results in decreased cell-cycle progression and enhanced apoptosis in a large proportion of cells. This inhibition of T cell proliferation can be rescued completely with anti-CD28 or IL-2 and partially with TGF-beta antagonists. This study reveals a functional role for CD80, CD86, and CTLA4 on CD4(+) T lymphocytes and sheds light on the mechanisms by which these molecules enhance activation and survival with PMA and ionomycin.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore, India.
authors.forename: Sambuddho
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Prasanta K
authors.initials: PK
authors.lastname: Maiti
authors.forename: Dipankar
authors.initials: D
authors.lastname: Nandi
mesh_terms: D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017209:Apoptosis; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D002453:Cell Cycle; D002470:Cell Survival; D002478:Cells, Cultured; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D000509:alpha-Fetoproteins / Q000494:pharmacology
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D007476:Ionophores; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D000509:alpha-Fetoproteins; D015759:Ionomycin; D000069594:Abatacept; D013755:Tetradecanoylphorbol Acetate