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Sci Rep. 2016 Dec 22;6:39796. doi: 10.1038/srep39796.

A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection.

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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.
Department of Translational Inflammation Research, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany.
Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.


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/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.

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