Principal Investigator:

Regulation of T cell immunity by innate signals
during poxvirus infection

The project aims to identify and characterize the interactions of innate and adaptive immunity which are required for the efficient activation of antigen-specific cytotoxic CD8+ T cells (CTL) by vaccinia virus (VACV). We recently identified a critical role of STING for type I interferon production and maturation of bone marrow-derived dendritic cells (BMDC) triggered in vitro by poxviral DNA, which also affected the activation and expansion of virus-induced CTL in vivo. In vitro, cross-presentation of viral antigens by non-infected BMDC strictly depended on viral DNA replication in infected feeder cells, which served as antigenic source. Since cross-presentation is the major pathway for generation of CTL by an highly attenuated VACV strain used as vaccine, we will investigate the signaling pathways which lead to the activation of BMDC by infected feeder cells and license them for efficient cross-presentation of antigens. We will perform a comparative systemic approach analyzing the transcriptome of infected feeder cells in which either viral DNA replication is inhibited (e.g. AraC-treatment) or DNA-sensing and type I IFN-production is impaired (e.g. STING Ko vs. wt cells). We will use VACV strains or mutants differing in virulence, immunomodulatory potential or antigen expression pattern and test their capacity to stimulate T cells in presence or absence of specific innate sensors (e.g. STING, cGAS, IFI16) or effector pathways (e.g. type I IFN) in vitro or in vivo during infection or vector-based vaccination which are particularly related to the response to viral DNA.

Publications

Muschaweckh, A, Buchholz, V, Fellenzer, A, Hessel, C, König, P, Tao, S, Tao, R, Heikenwälder, M, Busch, D, Korn, T, Kastenmüller, W, Drexler,I* and Gasteiger, G*. Antigen-dependent cross-competition shapes the local repertoire of resident memory CD8+ T cells in the skin. J Exp Med. 2016;213, 3075-3086. (*equal contribution)

Thiele F, Tao, S, Zhang Y, Muschaweckh A, Zollmann T, Protzer U, Abele, R, and Drexler, I. MVA-infected dendritic cells present CD4+ T cell epitopes by endogenous MHC class II presentation pathways. J Virol. 2015;89: 2698-2709.

Dai, P, Wang, W, Cao, H, Avogdadri, F, Vance, R, Dai, L, Drexler, I, Joyce, JA, Li, XD, Chen, Z, Merghoub, T, Shuman, S, and Deng, L. Modified Vaccinia Virus Ankara Triggers Type I IFN Production in Murine Conventional Dendritic Cells via a cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway. PLos Pathog. 2014 Apr 17;10(4):e1003989. doi: 10.1371/journal.ppat.1003989.

Eitz Ferrer P, Potthoff S, Kirschnek S, Gasteiger G, Kastenmuller W, Ludwig H, Paschen SA, Villunger A, Sutter G, Drexler I, Hacker G. Induction of Noxa-mediated apoptosis by modified vaccinia virus Ankara depends on viral recognition by cytosolic helicases, leading to IRF-3/IFN-beta-dependent induction of pro-apoptotic Noxa. PLoS Pathog. 2011;7:e1002083.

Pascutti MF, Rodriguez AM, Falivene J, Giavedoni L, Drexler I, Gherardi MM. Interplay between modified vaccinia virus Ankara and dendritic cells: phenotypic and functional maturation of bystander dendritic cells. J Virol. 2011;85:5532-45.

Moutaftsi M, Tscharke DC, Vaughan K, Koelle DM, Stern L, Calvo-Calle M, Ennis F, Terajima M, Sutter G, Crotty S, Drexler I, Franchini G, Yewdell JW, Head SR, Blum J, Peters B, Sette A. Uncovering the interplay between CD8, CD4 and antibody responses to complex pathogens. Future Microbiol. 2010;5:221-39.

Kastenmuller W, Gasteiger G, Stross L, Busch DH, Drexler I. Cutting edge: mucosal application of a lyophilized viral vector vaccine confers systemic and protective immunity toward intracellular pathogens. J Immunol. 2009;182:2573-7.

Gasteiger G, Kastenmuller W, Ljapoci R, Sutter G, Drexler I. Cross-priming of cytotoxic T cells dictates antigen requisites for modified vaccinia virus Ankara vector vaccines. J Virol. 2007;81:11925-36.

Kastenmuller W, Gasteiger G, Gronau JH, Baier R, Ljapoci R, Busch DH, Drexler I. Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination. J Exp Med. 2007;204:2187-98.

Drexler I, Staib C, Kastenmuller W, Stevanovic S, Schmidt B, Lemonnier FA, Rammensee HG, Busch DH, Bernhard H, Erfle V, Sutter G. Identification of vaccinia virus epitope-specific HLA-A*0201-restricted T cells and comparative analysis of smallpox vaccines. Proc Natl Acad Sci U S A. 2003;100:217-22.