Universität zu Köln

Elsner, Carina ORCID: 0000-0001-6590-8413, Ponnurangam, Aparna, Kazmierski, Julia ORCID: 0000-0002-7962-2165, Zillinger, Thomas ORCID: 0000-0002-0866-4835, Jansen, Jenny, Todt, Daniel ORCID: 0000-0002-3564-1014, Doehner, Katinka, Xu, Shuting, Ducroux, Aurelie, Kriedemann, Nils, Malassa, Angelina, Larsen, Pia-Katharina, Hartmann, Gunther, Barchet, Winfried ORCID: 0000-0002-6745-6606, Steinmann, Eike ORCID: 0000-0002-3654-9965, Kalinke, Ulrich, Sodeik, Beate ORCID: 0000-0003-4650-3036 and Goffinet, Christine ORCID: 0000-0002-3959-004X (2020). Absence of cGAS-mediated type I IFN responses in HIV-1-infected T cells. Proc. Natl. Acad. Sci. U. S. A., 117 (32). S. 19475 - 19487. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

The DNA sensor cGAS catalyzes the production of the cyclic dinucleotide cGAMP, resulting in type I interferon responses. We addressed the functionality of cGAS-mediated DNA sensing in human and murine T cells. Activated primary CD4(+) T cells expressed cGAS and responded to plasmid DNA by upregulation of ISGs and release of bioactive interferon. In mouse T cells, cGAS KO ablated sensing of plasmid DNA, and TREX1 KO enabled cells to sense short immunostimulatory DNA. Expression of IFIT1 and MX2 was downregulated and upregulated in cGAS KO and TREX1 KO T cell lines, respectively, compared to parental cells. Despite their intact cGAS sensing pathway, human CD4(+) T cells failed to mount a reverse transcriptase (RT) inhibitor-sensitive immune response following HIV-1 infection. In contrast, infection of human T cells with HSV-1 that is functionally deficient for the cGAS antagonist pUL41 (HSV-1 Delta UL41N) resulted in a cGAS-dependent type I interferon response. In accordance with our results in primary CD4(+) T cells, plasmid challenge or HSV-1 Delta UL41N inoculation of T cell lines provoked an entirely cGAS-dependent type I interferon response, including IRF3 phosphorylation and expression of ISGs. In contrast, no RT-dependent interferon response was detected following transduction of T cell lines with VSV-G-pseudotyped lentiviral or gammaretroviral particles. Together, T cells are capable to raise a cGAS-dependent cell-intrinsic response to both plasmid DNA challenge or inoculation with HSV-1 Delta UL41N. However, HIV-1 infection does not appear to trigger cGAS-mediated sensing of viral DNA in T cells, possibly by revealing viral DNA of insufficient quantity, length, and/or accessibility to cGAS.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Elsner, Carina UNSPECIFIED orcid.org/0000-0001-6590-8413 UNSPECIFIED Ponnurangam, Aparna UNSPECIFIED UNSPECIFIED UNSPECIFIED Kazmierski, Julia UNSPECIFIED orcid.org/0000-0002-7962-2165 UNSPECIFIED Zillinger, Thomas UNSPECIFIED orcid.org/0000-0002-0866-4835 UNSPECIFIED Jansen, Jenny UNSPECIFIED UNSPECIFIED UNSPECIFIED Todt, Daniel UNSPECIFIED orcid.org/0000-0002-3564-1014 UNSPECIFIED Doehner, Katinka UNSPECIFIED UNSPECIFIED UNSPECIFIED Xu, Shuting UNSPECIFIED UNSPECIFIED UNSPECIFIED Ducroux, Aurelie UNSPECIFIED UNSPECIFIED UNSPECIFIED Kriedemann, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Malassa, Angelina UNSPECIFIED UNSPECIFIED UNSPECIFIED Larsen, Pia-Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Gunther UNSPECIFIED UNSPECIFIED UNSPECIFIED Barchet, Winfried UNSPECIFIED orcid.org/0000-0002-6745-6606 UNSPECIFIED Steinmann, Eike UNSPECIFIED orcid.org/0000-0002-3654-9965 UNSPECIFIED Kalinke, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Sodeik, Beate UNSPECIFIED orcid.org/0000-0003-4650-3036 UNSPECIFIED Goffinet, Christine UNSPECIFIED orcid.org/0000-0002-3959-004X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-323491
DOI:	10.1073/pnas.2002481117
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	117
Number:	32
Page Range:	S. 19475 - 19487
Date:	2020
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HERPES-SIMPLEX-VIRUS; ALPHA-INTERFERON; IMMUNITY SPREADS; NUCLEAR IMPORT; DNA; HIV-1; INFECTION; SENSOR; CAPSIDS; GENES Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32349