title: A20 Curtails Primary but Augments Secondary CD8+T Cell Responses in Intracellular Bacterial Infection.
abstract: The ubiquitin-modifying enzyme A20, an important negative feedback regulator of NF-κB, impairs the expansion of tumor-specific CD8+T cells but augments the proliferation of autoimmune CD4+T cells. To study the T cell-specific function of A20 in bacterial infection, we infected T cell-specific A20 knockout (CD4-Cre A20fl/fl) and control mice with Listeria monocytogenes. A20-deficient pathogen-specific CD8+T cells expanded stronger resulting in improved pathogen control at day 7 p.i. Imaging flow cytometry revealed that A20-deficient Listeria-specific CD8+T cells underwent increased apoptosis and necroptosis resulting in reduced numbers of memory CD8+T cells. In contrast, the primary CD4+T cell response was A20-independent. Upon secondary infection, the increase and function of pathogen-specific CD8+T cells, as well as pathogen control were significantly impaired in CD4-Cre A20fl/flmice. In vitro, apoptosis and necroptosis of Listeria-specific A20-deficient CD8+T cells were strongly induced as demonstrated by increased caspase-3/7 activity, RIPK1/RIPK3 complex formation and more morphologically apoptotic and necroptotic CD8+T cells. In vitro, A20 limited CD95L and TNF-induced caspase3/7 activation. In conclusion, T cell-specific A20 limited the expansion but reduced apoptosis and necroptosis of Listeria-specific CD8+T cells, resulting in an impaired pathogen control in primary but improved clearance in secondary infection.
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Sissy
authors.initials: S
authors.lastname: Just
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.|Organ-specific Immune Regulation, Helmholtz-Center for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Gopala
authors.initials: G
authors.lastname: Nishanth
authors.affiliation: Department of Translational Inflammation Research, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany.
authors.forename: Jörn H
authors.initials: JH
authors.lastname: Buchbinder
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
authors.affiliation: Department of Translational Inflammation Research, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany.
authors.forename: Inna
authors.initials: I
authors.lastname: Lavrik
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.|Organ-specific Immune Regulation, Helmholtz-Center for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D007111:Immunity, Cellular; D007156:Immunologic Memory; D008087:Listeria / Q000276:immunology*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics / Q000276:immunology*
chemical_list: D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C513261:Tnfaip3 protein, mouse