The major research topic of our group is the study of the immune control of cytomegalovirus (CMV) infection in a mouse model. Control of CMV infection is dominated by CD8 T cells which are able to control the infection, but which are not able to clear the virus from the infected host. Our work aims at understanding this highly balanced virus host relationship under different immunological conditions.
In particular, after bone marrow transplantation (BMT), primary or recurrent CMV infections imperil the survival of the transplant recipients. To understand the underlying mechanisms we established an experimental murine BMT model, in which a concurrent infection with murine CMV (mCMV) is eventually controlled by endogenously reconstituted CD8 T cells preventing lethal multiple organ disease [Holtappels et al., 2004; 2013; 2016; Ebert et al., 2014; Nauerth et al., 2013]. The immune response, however, is not efficient in precluding morbidity and in clearance of the viral genome. This bears the risk of productive virus reactivation under immunocompromising conditions.
The limited efficiency of the antiviral immune response is explained in part by the expression of viral immune evasion proteins that interfere with the MHC class-I pathway of antigen presentation in infected cells [Fink et al., 2012; Holtappels et al., 2004; 2009]. Accordingly, deletion of the corresponding immune evasion genes reduces latent viral DNA burden and the incidence of virus recurrence.
In recent years, another component of the immune system involved in immune control of CMV infection came into the focus of experimental and clinical research. Regulatory T cells (Tregs) proved to impair immunity to CMV infection with CD4 Tregs being in the center of interest [Chopra et al., 2016]. However, their impact on the immune control of CMV infection, especially on protective antiviral CD8 T cells remains elusive.
Even less is known about the significance of another population of potentially suppressive T cells, namely the recently described CD8 Tregs. It is commonly accepted, that innate and adaptive immunity in general can be modulated by CD4 Tregs, whereas the significance and phenotype of CD8 Tregs is still a matter of debate.
In general, only few data exist on if and to what extent Tregs, CD8 Tregs in particular, may dampen and retard the reconstitution of the mCMV-specific CD8 T-cell response after BMT with the consequence of increased latent viral burden and the risk of reactivation. Therefore, we investigate the importance of CD8 Tregs as compared to CD4 Tregs in suppression of effector T cells in response to mCMV in vitro and in vivo.
An improved understanding of Treg function during mCMV infection, in particular in the context of BMT, is of fundamental relevance for the development of cell-based therapeutic approaches.
Immune control of mCMV infection after experimental bone marrow transplantation (BMT).
Significance of immunodominant CD8 T-cell specificities for the immune control of mCMV infection.
Significance of the avidity of CD8 T cells with respect to their protective potential.
Significance of vRAPs (viral Regulators of Antigen Presentation) on peptide presentation, T-cell priming, and immune control.
Influence of CMV in the development of allergic airway disease [Reuter et al., 2019].
References (*equal contribution)
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.
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 lungs. PLoS Pathog 10: e1004100.
Fink A, Lemmermann NA, Gillert-Marien D, Thomas D, Freitag K, Böhm V, Wilhelmi V, Reifenberg K, Reddehase MJ, Holtappels R (2012) Antigen presentation under the influence of 'immune evasion' proteins and its modulation by interferon-gamma: implications for immunotherapy of cytomegalovirus infection with antiviral CD8 T cells. Med Microbiol Immunol 201: 513-25.
Holtappels R, Ebert S, Podlech J, Fink A, Böhm V, Lemmermann NA, Freitag K, Renzaho A, Thomas D, Reddehase MJ (2013) Murine model for cytoimmuntherapy of CMV disease after hematopoietic cell transplantation. In: Cytomegaloviruses: from molecular pathogenesis to intervention. Edited by Reddehase M.J., Volume II, Chapter 17. Caister Academic Press, Norfolk, UK, pp 354-81.
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.
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.
Holtappels R, Thomas D, Reddehase MJ (2009) The efficacy of antigen processing is critical for protection against cytomegalovirus disease in the presence of viral immune evasion proteins. J Virol. 83: 9611-5.
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.
Reuter S*, Lemmermann NAW*, Maxeiner J, Podlech J, Beckert H, Freitag K, Teschner D, Ries F, Taube C, Buhl R, Reddehase MJ*, Holtappels R* (2019) Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells. PLoS Pathog 15:e1007595.