Immunmodulation of cytomegalovirus latency and reactivation by regulatory T cells and dendritic cells
Abstract:
After bone marrow transplantation (BMT), cytomegalovirus (CMV) infections imperil the survival of transplant recipients as the immune response is not efficient in preventing morbidity and clearance of the virus. We plan to investigate the role of regulatory T cells (Tregs), of CD8 Tregs in particular, in suppression of protective CD8 T cells in response to murine CMV after BMT. Furthermore, we will study how dendritic cells (DCs) contribute to the generation and function of Tregs. An improved understanding of the role of Tregs and their interaction with DCs in the context of BMT and CMV infection is of fundamental importance for the development of cell-based therapeutic approaches.
Principal investigators:
Prof. apl. Dr. rer. nat. et med. habil. Rafaela Holtappels
Institut für Virologie
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Obere Zahlbacher Straße 67, 55131 Mainz
Phone: +49 (0)6131 17-9309
E-mail: R.Holtappels@uni-mainz.de
Web: http://www.unimedizin-mainz.de/virologie/research/research-groups/ag-holtappels.html
Univ.-Prof. Dr. rer. nat. Björn Clausen
Institut für Molekulare Medizin
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Obere Zahlbacher Straße 67, 55131 Mainz
Phone: +49 (0)6131 17-2204
E-mail: bclausen@uni-mainz.de
Web: http://www.unimedizin-mainz.de/molekulare-medizin/arbeitsgruppen/ag-clausen.html
Doctoral candidates:
Sara Hamdan
Josephin Schwarz
Project-related publications:
Chopra M, Biehl M, Steinfatt T, Brandl A, Kums J, Amich J, Vaeth M, Kuen J, Holtappels R, Podlech J, Mottok A, Kraus S, Jordán-Garrote AL, Bäuerlein CA, Brede C, Ribechini E, Fick A, Seher A, Polz J, Ottmüller KJ, Baker J, Nishikii H, Ritz M, Mattenheimer K, Schwinn S, Winter T, Schäfer V, Krappmann S, Einsele H, Müller TD, Reddehase MJ, Lutz MB, Männel DN, Berberich-Siebelt F, Wajant H, Beilhack A (2016) Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion. J Exp Med 213: 1881-900.
Holtappels R, Lemmermann NA, Podlech J, Ebert S, Reddehase MJ (2016) Reconstitution of CD8 T cells protective against cytomegalovirus in a mouse model of hematopoietic cell transplantation: dynamics and inessentiality of epitope immunodominance. Front Immunol 7: 232.
Girard-Madoux MJ, Kautz-Neu K, Lorenz B, Ober-Blöbaum JL, von Stebut E*, Clausen BE* (2015) IL-10 signaling in dendritic cells attenuates anti-Leishmania major immunity without affecting protective memory responses. J Invest Dermatol 135: 2890-4.
Fu C, Liang X, Cui W, Ober-Blöbaum JL, Vazzana J, Shrikant PA, Lee KP, Clausen BE, Mellman I, Jiang A (2015) β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci USA 112: 2823-8.
Liang X, Fu C, Cui W, Ober-Blöbaum JL, Zahner SP, Shrikant PA, Clausen BE, Flavell RA, Mellman I, Jiang A (2014) β-catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8⁺ T cells. J Leukoc Biol 95: 179-90.
Ebert S*, Becker M *, Lemmermann NAW, 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 lungshttps://www.ncbi.nlm.nih.gov/pubmed/24763809. PLoS Pathog 10: e1004100.
Nauerth M, Weißbrich B, Knall R, Franz T, Dössinger G, Bet J, Paszkiewicz PJ, Pfeifer L, Bunse M, Uckert W, Holtappels R, Gillert-Marien D, Neuenhahn M, Krackhardt A, Reddehase MJ, Riddell SR, Busch DH (2013) TCR-ligand koff rate correlates with the protective capacity of antigen-specific CD8+ T cells for adoptive transfer. Sci Transl Med 5192: 192ra87.
Mandaric S, Walton SM, Rülicke T, Richter K, Girard-Madoux MJ, Clausen BE, Zurunic A, Kamanaka M, Flavell RA, Jonjic S, Oxenius A (2012) IL-10 suppression of NK/DC crosstalk leads to poor priming of MCMV-specific CD4 T cells and prolonged MCMV persistence. PLoS Pathog 8: e1002846.
Girard-Madoux MJ, Kel JM, Reizis B, Clausen BE (2012) IL-10 controls DC-induced T-cell reactivation in the skin to limit contact hypersensitivity. J Allergy Clin Immunol 129: 143-50.e1-10.
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: 131-6.