Browsing publications of the scientific administration (GFW) by Authors
A20 Curtails Primary but Augments Secondary CD8(+) T Cell Responses in Intracellular Bacterial Infection.Just, Sissy; Nishanth, Gopala; Buchbinder, Jörn H; Wang, Xu; Naumann, Michael; Lavrik, Inna; Schlüter, Dirk; Helmholtz Centre for infection research, Inhoffenstr. 7., 38124 Braunschweig, Germany. (2016-12-22)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 A20(fl/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 A20(fl/fl) mice. 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.
OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes.Wang, Xu; Mulas, Floriana; Yi, Wenjing; Brunn, Anna; Nishanth, Gopala; Just, Sissy; Waisman, Ari; Brück, Wolfgang; Deckert, Martina; Schlüter, Dirk; et al. (EMBO Press, 2019-04-03)Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell-intrinsic mechanism governing astrocyte function during MS and EAE Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE Mice with astrocyte-specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1-deficient astrocytes were hyperactivated in response to IFN-γ, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN-γ-induced Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS1). Thus, astrocyte-specific OTUB1 is a critical inhibitor of neuroinflammation in CNS autoimmunity.