title: Inhibition of superoxide generation upon T-cell receptor engagement rescues Mart-1(27-35)-reactive T cells from activation-induced cell death.
abstract: Cytotoxic T lymphocytes (CTL) may undergo massive expansion upon appropriate antigenic stimulation. Homeostasis is maintained by a subsequent "contraction" of these cells. Activation-induced cell death (AICD) and programmed cell death prevent the untoward side effects, arising from excessive numbers and prolonged persistence of activated CTL, that occur upon uncontrolled and/or continued expansion. However, effector cell persistence has been identified as a hallmark of successful T-cell-mediated adoptive immunotherapy. Thus, prevention of AICD may be critical to achieve more successful clinical results. We have previously shown that treatment with the c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125 protects human melanoma epitope Mart-1(27-35)-reactive CTL from apoptotic death upon their reencounter with cognate antigen. However, inhibition of JNK also interferes with the functional ability of the CTL to secrete IFN-gamma. Here, we show that reactive oxygen species (ROS) inhibitors, such as the superoxide dismutase mimetic Mn (III) tetrakis (5, 10, 15, 20-benzoic acid) porphyrin (MnTBAP), efficiently protected Mart-1(27-35)-reactive primary CTL from AICD without impairing their functional capability. MnTBAP prevented the increase in intracellular ROS, mitochondrial membrane collapse, and DNA fragmentation observed in control-treated cells upon cognate antigen encounter. Furthermore, the mechanism of AICD prevention in primary CTL included blockade of JNK activation. Finally, tumor-reactive in vitro expanded tumor infiltrating lymphocytes, which are used clinically in cancer immunotherapy, also benefit from MnTBAP-mediated antioxidant treatment. Thus, modulation of the redox pathway might improve CTL persistence and lead to better clinical results for T cell-based immunotherapies.
authors.affiliation: Departments of Surgery, Microbiology and Immunology, and Pathology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Håkan
authors.initials: H
authors.lastname: Norell
authors.forename: Telma
authors.initials: T
authors.lastname: Martins da Palma
authors.forename: Aaron
authors.initials: A
authors.lastname: Lesher
authors.forename: Navtej
authors.initials: N
authors.lastname: Kaur
authors.forename: Meenal
authors.initials: M
authors.lastname: Mehrotra
authors.forename: Osama S
authors.initials: OS
authors.lastname: Naga
authors.forename: Natalie
authors.initials: N
authors.lastname: Spivey
authors.forename: Seye
authors.initials: S
authors.lastname: Olafimihan
authors.forename: Nitya G
authors.initials: NG
authors.lastname: Chakraborty
authors.forename: Christina
authors.initials: C
authors.lastname: Voelkel-Johnson
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.forename: Bijay
authors.initials: B
authors.lastname: Mukherji
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000276:immunology; D008665:Metalloporphyrins / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000276:immunology*; D009975:Orthomyxoviridae / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D016166:Free Radical Scavengers; D015789:HLA-A2 Antigen; C105787:MART-1-Melan-A(27-35) epitope; D008665:Metalloporphyrins; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D014763:Viral Matrix Proteins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D013481:Superoxides