Visual Universitätsmedizin Mainz

Viral modulation of innate and adaptive immune cells and ‚inbetweeners‘

Evasion of innate and adaptive immune responses is a common feature of tumors and chronic viral infections. An active interference with the presentation of antigenic peptides by MHC class-I and -II molecules is a strategy to prevent altered-self/non-self recognition by CD8 and CD4 T cells. Downregulation and upregulation of ligands of activatory and inhibitory recep­tors, respectively, is a strategy to silence natural killer (NK) cells. At the innate-adaptive immunity interface, downregulation of self and foreign lipid-presenting CD1d molecules is a means to evade invariant NKT (iNKT) cells, ‘inbetweeners’ acting as instant regulators of clas­sically innate and classically adaptive immune responses. 

The project aims at identifying mech­anisms by which viral genes modulate the immune response as well as mechanisms by which the host can regulate the expression of these viral immune modulators. Learning how the host eventually manages to keep a chronic virus in check irrespective of its immune evasion strate­gies may reveal concepts of how to improve immune surveillance also of malignant cells.

This project is founded by the DFG within the CRC 1292 TP11

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Research Objectives

Objective 1: Novel and revised mechanisms of CMV immune evasion

mCMV only modestly and indirectly activates iNKT cells, which likely relates to an iNKT evasion of wild-type virus. We could indeed show in cell culture that mCMV infection downmod­u­lates the iNKT cell ligand CD1d, a strategy also used by tumors for silencing iNKT cells. We propose to identify the responsible viral gene.  Once the gene is identi­fied, mutant and revertant viruses will be generated to study the role of iNKT cells and iNKT cell silencing in established CMV disease models.

Based on the finding that deletion of the viral immunoevasin m06/gp48 results in the activation of NK cells, we propose that this protein binds to and thereby down modulates a cellular or viral ligand of an NK cell receptor. After identification of the interactome of m06 the corresponding NK cell receptor will be identified as well, thus further analyzing the role of CMV immune evasion for establishment of latency. 

Objective 2: Type I-IFN regulation of immune evasion gene expression

As a result of co-speciation, mCMV has evolved genes to evade immune control, while the host has evolved mechanisms to counteract viral immune evasion, the net result of which is prevention of lethal acute infection/disease and a moderated chronic or even latent infection. We have discovered a highly conserved interferon response factor element (IRFE) in the pro­moter region of viral gene m152 through which type-I IFNs can control m152 gene expression for modu­lating the degree of RAE-1 and peptide-MHC-I downregulation. We will generate IRFE mutant and revertant viruses incompetent and competent, respectively, in type-I IFN signaling to the m152 promoter and will study these viruses for RAE-1 and peptide-MHC-I downregulation and for NK cell and CD8 T cell evasion in immunocompetent mice as well as in immuno­compromised host, hematopoietic cell transplantation (HCT), and adoptive cell transfer (immuno­therapy) models for which our group is internationally renowned.

 

Project related publications

 

Reddehase MJ 2016. Mutual interference between cytomegalovirus and reconstitution of protective immunity after hematopoietic cell transplantation. Front Immunol 7:294

Fink A, Blaum F, Babic Cac M, Ebert S, Lemmermann NA, Reddehase MJ 2015. An endocytic YXXΦ (YRRF) cargo sorting motif in the cytoplasmic tail of murine cytomegalovirus AP2 'adapter adapter' protein m04/gp34 antagonizes virus evasion of natural killer cells. Med Microbiol Immunol 204:383-394

Lemmermann NA*, Krmpotic A*, Podlech J*, Brizic I, Prager A, Adler H, Karbach A, Wu Y, Jonjic S, Reddehase MJ*, Adler B* 2015. Non-redundant and redundant roles of cytomegalovirus gH/gL complexes in host organ entry and intra-tissue spread. PLoS Pathog 11:e1004640

Thomas S, Klobuch S, Podlech J, Plachter B, Hoffmann P, Renzaho A, Theobald M, Reddehase MJ*, Herr W*, Lemmermann NA* 2015. Evaluating human T-cell therapy of cytomegalovirus organ disease in HLA-transgenic mice. PLoS Pathog 11:e1005049

Ebert, S, Becker M, Lemmermann NA, Büttner JK, Michel A, Taube C, Podlech J, Böhm V, Freitag K, Thomas D, Holtappels R*, Reddehase MJ*, Stassen M* 2014. Mast cells expedite control of pulmonary murine cytomegalovirus infection by enhancing the recruitment of protective CD8 T cells to the lungs. PLoS Pathog 10: e1004100

Fink, A, Renzaho A, Reddehase MJ*, Lemmermann NA* 2013. The p36 isoform of murine cytomegalovirus m152 protein suffices for mediating innate and adaptive immune evasion. Viruses 5: 3171-3191

Lemmermann NA*, Fink A*, Podlech J, Ebert S, Wilhelmi V, Böhm V, Holtappels R, Reddehase MJ 2012. Murine cytomegalovirus immune evasion proteins operative in the MHC class I pathway of antigen processing and presentation: state of knowledge, revisions, and questions. Med Microbiol Immunol 201:497-512

Wilhelmi V, Simon CO, Podlech J, Böhm V, Däubner T, Emde S, Strand D, Renzaho A, Lemmermann NA, Seckert CK, Reddehase MJ*, Grzimek NK 2008. Transactivation of cellular genes involved in nucleotide metabolism by the regulatory IE1 protein of murine cytomegalovirus is not critical for viral replicative fitness in quiescent cells and host tissues. J Virol 82:9900-9916

Holtappels R, Podlech J, Pahl-Seibert MF, Jülch M, Thomas D, Simon CO, Wagner M, Reddehase MJ 2004.Cytomegalovirus misleads its host by priming of CD8 T cells specific for an epitope not presented in infected tissues. J Exp Med 199:131-136

Reddehase MJ 2002. Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Rev Immunol 2: 831-844