Protective dendritic cell responses against listeriosis induced by the short form of the deubiquitinating enzyme CYLD are inhibited by full‐length CYLD

• Published in: European journal of immunology 2015-05, Vol.45 (5), p.1366-1376
• Main Authors: Wurm, Rebecca, Just, Sissy, Wang, Xu, Wex, Katharina, Schmid, Ursula, Blanchard, Nicolas, Waisman, Ari, Schild, Hans‐Jörg, Deckert, Martina, Naumann, Michael, Schlüter, Dirk, Nishanth, Gopala
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation; CD11c Antigen - genetics; CD11c Antigen - metabolism; CD8 Antigens - metabolism; CD8-Positive T-Lymphocytes - immunology; CYLD; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - immunology; Cytokines - biosynthesis; Dendritic cell; Dendritic Cells - enzymology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Histocompatibility Antigens Class I - metabolism; Infection; Isoenzymes - genetics; Isoenzymes - immunology; Killer Cells, Natural - immunology; Leukocytes - immunology; Leukocytes - pathology; Listeria; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeria monocytogenes - isolation & purification; Listeria monocytogenes - pathogenicity; Listeriosis - enzymology; Listeriosis - immunology; Listeriosis - microbiology; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; NF-kappa B - metabolism; Spleen - immunology; Spleen - pathology; Up-Regulation
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201445116

The deubiquitinating enzyme CYLD is an important tumor suppressor and inhibitor of immune responses. In contrast to full‐length CYLD, the immunological function of the naturally occurring short splice variant of CYLD (sCYLD) is insufficiently described. Previously, we showed that DCs, which lack full‐length CYLD but express sCYLD, exhibit augmented NF‐κB and DC activation. To explore the function of sCYLD in infection, we investigated whether DC‐specific sCYLD regulates the pathogenesis of listeriosis. Upon Listeria monocytogenes infection of CD11c‐Cre Cyldex7/8 fl/fl mice, infection of CD8α+ DCs, which are crucial for the establishment of listeriosis in the spleen, was not affected. However, NF‐κB activity of CD11c‐Cre Cyldex7/8 fl/fl DCs was increased, while activation of ERK and p38 was normal. In addition, CD11c‐Cre Cyldex7/8 fl/fl DCs produced more TNF, IL‐10, and IL‐12 upon infection, which led to enhanced stimulation of IFN‐γ‐producing NK cells. In addition CD11c‐Cre Cyldex7/8 fl/fl DCs presented Listeria Ag more efficiently to CD8+ T cells resulting in a stronger pathogen‐specific CD8+ T‐cell proliferation and more IFN‐γ production. Collectively, the improved innate and adaptive immunity and survival during listeriosis identify the DC‐specific FL‐CYLD/sCYLD balance as a potential target to modulate NK‐cell and Ag‐specific CD8+ T‐cell responses.