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Rafaela Holtappels
Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

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Review
Published: 03 August 2021 in Viruses
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Hematopoietic cell (HC) transplantation (HCT) is the last resort to cure hematopoietic malignancies that are refractory to standard therapies. Hematoablative treatment aims at wiping out tumor cells as completely as possible to avoid leukemia/lymphoma relapse. This treatment inevitably co-depletes cells of hematopoietic cell lineages, including differentiated cells that constitute the immune system. HCT reconstitutes hematopoiesis and thus, eventually, also antiviral effector cells. In cases of an unrelated donor, that is, in allogeneic HCT, HLA-matching is performed to minimize the risk of graft-versus-host reaction and disease (GvHR/D), but a mismatch in minor histocompatibility antigens (minor HAg) is unavoidable. The transient immunodeficiency in the period between hematoablative treatment and reconstitution by HCT gives latent cytomegalovirus (CMV) the chance to reactivate from latently infected donor HC or from latently infected organs of the recipient, or from both. Clinical experience shows that HLA and/or minor-HAg mismatches increase the risk of complications from CMV. Recent results challenge the widespread, though never proven, view of a mechanistic link between GvHR/D and CMV. Instead, new evidence suggests that histoincompatibility promotes CMV disease by inducing non-cognate transplantation tolerance that inhibits an efficient reconstitution of high-avidity CD8+ T cells capable of recognizing and resolving cytopathogenic tissue infection.

ACS Style

Matthias Reddehase; Rafaela Holtappels; Niels Lemmermann. Consequence of Histoincompatibility beyond GvH-Reaction in Cytomegalovirus Disease Associated with Allogeneic Hematopoietic Cell Transplantation: Change of Paradigm. Viruses 2021, 13, 1530 .

AMA Style

Matthias Reddehase, Rafaela Holtappels, Niels Lemmermann. Consequence of Histoincompatibility beyond GvH-Reaction in Cytomegalovirus Disease Associated with Allogeneic Hematopoietic Cell Transplantation: Change of Paradigm. Viruses. 2021; 13 (8):1530.

Chicago/Turabian Style

Matthias Reddehase; Rafaela Holtappels; Niels Lemmermann. 2021. "Consequence of Histoincompatibility beyond GvH-Reaction in Cytomegalovirus Disease Associated with Allogeneic Hematopoietic Cell Transplantation: Change of Paradigm." Viruses 13, no. 8: 1530.

Journal article
Published: 29 July 2021 in Pathogens
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CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target.

ACS Style

Kirsten Freitag; Sara Hamdan; Matthias Reddehase; Rafaela Holtappels. Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells. Pathogens 2021, 10, 956 .

AMA Style

Kirsten Freitag, Sara Hamdan, Matthias Reddehase, Rafaela Holtappels. Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells. Pathogens. 2021; 10 (8):956.

Chicago/Turabian Style

Kirsten Freitag; Sara Hamdan; Matthias Reddehase; Rafaela Holtappels. 2021. "Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells." Pathogens 10, no. 8: 956.

Journal article
Published: 22 July 2020 in Vaccines
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Murine models of cytomegalovirus (CMV) infection have revealed an exceptional kinetics of the immune response. After resolution of productive infection, transient contraction of the viral epitope-specific CD8 T-cell pool was found to be followed by a pool expansion specific for certain viral epitopes during non-productive ‘latent’ infection. This phenomenon, known as ‘memory inflation’ (MI), was found to be based on inflationary KLRG1+CD62L− effector-memory T cells (iTEM) that depend on repetitive restimulation. MI gained substantial interest for employing CMV as vaccine vector by replacing MI-driving CMV epitopes with foreign epitopes for generating high numbers of protective memory cells specific for unrelated pathogens. The concept of an MI-driving CMV vector is questioned by human studies disputing MI in humans. A bias towards MI in experimental models may have resulted from systemic infection. We have here studied local murine CMV infection as a route that is more closely matching routine human vaccine application. Notably, KLRG1−CD62L+ central memory T cells (TCM) and conventional KLRG1−CD62L− effector memory T cells (cTEM) were found to expand, associated with ‘avidity maturation’, whereas the pool size of iTEM steadily declined over time. The establishment of high avidity CD8 T-cell central memory encourages one to pursue the concept of CMV vector-based vaccines.

ACS Style

Rafaela Holtappels; Kirsten Freitag; Angelique Renzaho; Sara Becker; Niels A.W. Lemmermann; Matthias J. Reddehase. Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors. Vaccines 2020, 8, 402 .

AMA Style

Rafaela Holtappels, Kirsten Freitag, Angelique Renzaho, Sara Becker, Niels A.W. Lemmermann, Matthias J. Reddehase. Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors. Vaccines. 2020; 8 (3):402.

Chicago/Turabian Style

Rafaela Holtappels; Kirsten Freitag; Angelique Renzaho; Sara Becker; Niels A.W. Lemmermann; Matthias J. Reddehase. 2020. "Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors." Vaccines 8, no. 3: 402.

Research article
Published: 07 March 2019 in PLOS Pathogens
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Despite a broad cell-type tropism, cytomegalovirus (CMV) is an evidentially pulmonary pathogen. Predilection for the lungs is of medical relevance in immunocompromised recipients of hematopoietic cell transplantation, in whom interstitial CMV pneumonia is a frequent and, if left untreated, fatal clinical manifestation of human CMV infection. A conceivable contribution of CMV to airway diseases of other etiology is an issue that so far attracted little medical attention. As the route of primary CMV infection upon host-to-host transmission in early childhood involves airway mucosa, coincidence of CMV airway infection and exposure to airborne environmental antigens is almost unavoidable. For investigating possible consequences of such a coincidence, we established a mouse model of airway co-exposure to CMV and ovalbumin (OVA) representing a protein antigen of an inherently low allergenic potential. Accordingly, intratracheal OVA exposure alone failed to sensitize for allergic airway disease (AAD) upon OVA aerosol challenge. In contrast, airway infection at the time of OVA sensitization predisposed for AAD that was characterized by airway inflammation, IgE secretion, thickening of airway epithelia, and goblet cell hyperplasia. This AAD histopathology was associated with a T helper type 2 (Th2) transcription profile in the lungs, including IL-4, IL-5, IL-9, and IL-25, known inducers of Th2-driven AAD. These symptoms were all prevented by a pre-challenge depletion of CD4+ T cells, but not of CD8+ T cells. As to the underlying mechanism, murine CMV activated migratory CD11b+ as well as CD103+ conventional dendritic cells (cDCs), which have been associated with Th2 cytokine-driven AAD and with antigen cross-presentation, respectively. This resulted in an enhanced OVA uptake and recruitment of the OVA-laden cDCs selectively to the draining tracheal lymph nodes for antigen presentation. We thus propose that CMV, through activation of migratory cDCs in the airway mucosa, can enhance the allergenic potential of otherwise poorly allergenic environmental protein antigens. From an epidemiological perspective, natural host-to-host transmission of human CMV mostly occurs in early childhood through saliva from virus-shedding intimate contact persons, such as family members or peers. The oronasal route of transmission involves also the airway mucosa and airway-draining lymph nodes. Almost unavoidably, CMV airway infection coincides with airway exposure to environmental antigens, which include potent classical allergens but also protein antigens that have low-to-no allergenic potential on their own. Ovalbumin (OVA), when administered as a purified protein, can serve as a well-studied model antigen for only poorly allergenic environmental antigens. In a murine model of airway exposure to OVA for allergenic sensitization, we have addressed the question if a simultaneous airway infection with murine CMV (mCMV) can promote allergic airway disease (AAD) elicited by challenge exposure to OVA. As anticipated by the model design, exposure to OVA alone did not sensitize for an allergic response to challenge exposure, nor did mCMV infection alone. Notably, based on viral activation of antigen uptake by DCs, both combined sensitized for a type 2 CD4+ T helper (Th2) cell-driven AAD histopathology. This is a novel aspect in CMV pathobiology with the medical relevance that CMV airway infection enlarges the spectrum of environmental allergens.

ACS Style

Sebastian Reuter; Niels A. W. Lemmermann; Joachim Maxeiner; Jürgen Podlech; Hendrik Beckert; Kirsten Freitag; Daniel Teschner; Frederic Ries; Christian Taube; Roland Buhl; Matthias J. Reddehase; Rafaela Holtappels. Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells. PLOS Pathogens 2019, 15, e1007595 .

AMA Style

Sebastian Reuter, Niels A. W. Lemmermann, Joachim Maxeiner, Jürgen Podlech, Hendrik Beckert, Kirsten Freitag, Daniel Teschner, Frederic Ries, Christian Taube, Roland Buhl, Matthias J. Reddehase, Rafaela Holtappels. Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells. PLOS Pathogens. 2019; 15 (3):e1007595.

Chicago/Turabian Style

Sebastian Reuter; Niels A. W. Lemmermann; Joachim Maxeiner; Jürgen Podlech; Hendrik Beckert; Kirsten Freitag; Daniel Teschner; Frederic Ries; Christian Taube; Roland Buhl; Matthias J. Reddehase; Rafaela Holtappels. 2019. "Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells." PLOS Pathogens 15, no. 3: e1007595.

Journal article
Published: 15 August 2016 in Journal of Experimental Medicine
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Donor CD4+Foxp3+ regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT [allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2- and T reg cell–dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.

ACS Style

Martin Chopra; Marlene Biehl; Tim Steinfatt; Andreas Brandl; Juliane Kums; Jorge Amich; Martin Vaeth; Janina Kuen; Rafaela Holtappels; Jürgen Podlech; Anja Mottok; Sabrina Kraus; Ana-Laura Jordán-Garrote; Carina A. Bäuerlein; Christian Brede; Eliana Ribechini; Andrea Fick; Axel Seher; Johannes Polz; Katja J. Ottmüller; Jeanette Baker; Hidekazu Nishikii; Miriam Ritz; Katharina Mattenheimer; Stefanie Schwinn; Thorsten Winter; Viktoria Schäfer; Sven Krappmann; Hermann Einsele; Thomas D. Müller; Matthias Reddehase; Manfred B. Lutz; Daniela N. Männel; Friederike Berberich-Siebelt; Harald Wajant; Andreas Beilhack. Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion. Journal of Experimental Medicine 2016, 213, 1881 -1900.

AMA Style

Martin Chopra, Marlene Biehl, Tim Steinfatt, Andreas Brandl, Juliane Kums, Jorge Amich, Martin Vaeth, Janina Kuen, Rafaela Holtappels, Jürgen Podlech, Anja Mottok, Sabrina Kraus, Ana-Laura Jordán-Garrote, Carina A. Bäuerlein, Christian Brede, Eliana Ribechini, Andrea Fick, Axel Seher, Johannes Polz, Katja J. Ottmüller, Jeanette Baker, Hidekazu Nishikii, Miriam Ritz, Katharina Mattenheimer, Stefanie Schwinn, Thorsten Winter, Viktoria Schäfer, Sven Krappmann, Hermann Einsele, Thomas D. Müller, Matthias Reddehase, Manfred B. Lutz, Daniela N. Männel, Friederike Berberich-Siebelt, Harald Wajant, Andreas Beilhack. Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion. Journal of Experimental Medicine. 2016; 213 (9):1881-1900.

Chicago/Turabian Style

Martin Chopra; Marlene Biehl; Tim Steinfatt; Andreas Brandl; Juliane Kums; Jorge Amich; Martin Vaeth; Janina Kuen; Rafaela Holtappels; Jürgen Podlech; Anja Mottok; Sabrina Kraus; Ana-Laura Jordán-Garrote; Carina A. Bäuerlein; Christian Brede; Eliana Ribechini; Andrea Fick; Axel Seher; Johannes Polz; Katja J. Ottmüller; Jeanette Baker; Hidekazu Nishikii; Miriam Ritz; Katharina Mattenheimer; Stefanie Schwinn; Thorsten Winter; Viktoria Schäfer; Sven Krappmann; Hermann Einsele; Thomas D. Müller; Matthias Reddehase; Manfred B. Lutz; Daniela N. Männel; Friederike Berberich-Siebelt; Harald Wajant; Andreas Beilhack. 2016. "Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion." Journal of Experimental Medicine 213, no. 9: 1881-1900.

Journal article
Published: 25 March 2015 in Medical Microbiology and Immunology
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Control of murine cytomegalovirus (mCMV) infection is mediated primarily by CD8 T cells, with four specificities dominating in BALB/c mice. Functional deletion of the respective immunodominant epitopes (IDEs) in mutant virus Δ4IDE revealed a still efficient control of infection. In a murine model of hematopoietic cell transplantation and infection with Δ4IDE, an mCMV-specific open reading frame (ORF) library screening assay indicated a strong CD8 T cell reactivity against the ORF-M54 product, the highly conserved and essential mCMV homolog of human CMV DNA polymerase UL54, which is a known inducer of in vivo protection against mCMV by DNA immunization. Applying bioinformatic algorithms for CD8 T cell epitope prediction, the top-scoring peptides were used to stimulate ex vivo-isolated CD8 T cells and to generate cytolytic T cell lines; yet, this approach failed to identify M54 epitope(s). As an alternative, a peptide library consisting of 549 10-mers with an offset of two amino acids (aa), covering the complete aa-sequence of the M54 protein, was synthesized and used for the stimulation. A region of 12 aa proved to encompass an epitope. An 'alanine walk' over this antigenic 12-mer and all possible 11-, 10- and 9-mers derived thereof revealed aa-residues critical for antigenicity, and terminal truncations identified the H-2D(d) presented 8-mer M5483-90 as the optimal epitope. An increased frequency of the corresponding CD8 T cells in the absence of the 4 IDEs indicated immunodomination by the IDE-specific CD8 T cells as a mechanism by which the generation of M54-specific CD8 T cells is inhibited after infection with wild-type mCMV.

ACS Style

Rafaela Holtappels; Niels Lemmermann; Doris Thomas; Angélique Renzaho; Matthias Reddehase. Identification of an atypical CD8 T cell epitope encoded by murine cytomegalovirus ORF-M54 gaining dominance after deletion of the immunodominant antiviral CD8 T cell specificities. Medical Microbiology and Immunology 2015, 204, 317 -326.

AMA Style

Rafaela Holtappels, Niels Lemmermann, Doris Thomas, Angélique Renzaho, Matthias Reddehase. Identification of an atypical CD8 T cell epitope encoded by murine cytomegalovirus ORF-M54 gaining dominance after deletion of the immunodominant antiviral CD8 T cell specificities. Medical Microbiology and Immunology. 2015; 204 (3):317-326.

Chicago/Turabian Style

Rafaela Holtappels; Niels Lemmermann; Doris Thomas; Angélique Renzaho; Matthias Reddehase. 2015. "Identification of an atypical CD8 T cell epitope encoded by murine cytomegalovirus ORF-M54 gaining dominance after deletion of the immunodominant antiviral CD8 T cell specificities." Medical Microbiology and Immunology 204, no. 3: 317-326.

Journal article
Published: 14 February 2014 in Viruses
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Viral CD8 T-cell epitopes, represented by viral peptides bound to major histocompatibility complex class-I (MHC-I) glycoproteins, are often identified by “reverse immunology”, a strategy not requiring biochemical and structural knowledge of the actual viral protein from which they are derived by antigen processing. Instead, bioinformatic algorithms predicting the probability of C-terminal cleavage in the proteasome, as well as binding affinity to the presenting MHC-I molecules, are applied to amino acid sequences deduced from predicted open reading frames (ORFs) based on the genomic sequence. If the protein corresponding to an antigenic ORF is known, it is usually inferred that the kinetic class of the protein also defines the phase in the viral replicative cycle during which the respective antigenic peptide is presented for recognition by CD8 T cells. We have previously identified a nonapeptide from the predicted ORFm164 of murine cytomegalovirus that is presented by the MHC-I allomorph H-2 Dd and that is immunodominant in BALB/c (H-2d haplotype) mice. Surprisingly, although the ORFm164 protein gp36.5 is expressed as an Early (E) phase protein, the m164 epitope is presented already during the Immediate Early (IE) phase, based on the expression of an upstream mRNA starting within ORFm167 and encompassing ORFm164.

ACS Style

Annette Fink; Julia K. Büttner; Doris Thomas; Rafaela Holtappels; Matthias J. Reddehase; Niels A. W. Lemmermann. Noncanonical Expression of a Murine Cytomegalovirus Early Protein CD8 T-Cell Epitope as an Immediate Early Epitope Based on Transcription from an Upstream Gene. Viruses 2014, 6, 808 -831.

AMA Style

Annette Fink, Julia K. Büttner, Doris Thomas, Rafaela Holtappels, Matthias J. Reddehase, Niels A. W. Lemmermann. Noncanonical Expression of a Murine Cytomegalovirus Early Protein CD8 T-Cell Epitope as an Immediate Early Epitope Based on Transcription from an Upstream Gene. Viruses. 2014; 6 (2):808-831.

Chicago/Turabian Style

Annette Fink; Julia K. Büttner; Doris Thomas; Rafaela Holtappels; Matthias J. Reddehase; Niels A. W. Lemmermann. 2014. "Noncanonical Expression of a Murine Cytomegalovirus Early Protein CD8 T-Cell Epitope as an Immediate Early Epitope Based on Transcription from an Upstream Gene." Viruses 6, no. 2: 808-831.

Journal article
Published: 14 September 2012 in Medical Microbiology and Immunology
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Adoptive transfer of virus-specific donor-derived CD8 T cells is a therapeutic option to prevent cytomegalovirus (CMV) disease in recipients of hematopoietic cell transplantation. Due to their high coding capacity, human as well as animal CMVs have the potential to encode numerous CD8 T cell epitopes. Although the CD8 T cell response to CMVs is indeed broadly specific in that it involves epitopes derived from almost every open reading frame when tested for cohorts of immune CMV carriers representing the polymorphic MHC/HLA distribution in the population, the response in any one individual is directed against relatively few epitopes selected by the private combination of MHC/HLA alleles. Of this individually selected set of epitopes, few epitopes are ‘immunodominant’ in terms of magnitude of the response directed against them, while others are ‘subdominant’ according to this definition. In the assumption that ‘immunodominance’ indicates ‘relevance’ in antiviral control, research interest was focused on the immunodominant epitopes (IDEs) and their potential use in immunotherapy and in vaccines. The murine model has provided ‘proof of concept’ for the efficacy of CD8 T cell therapy of CMV infection. By experimental modulation of the CD8 T cell ‘immunome’ of murine CMV constructing an IDE deletion mutant, we have used this established cytoimmunotherapy model (a) for evaluating the actual contribution of IDEs to the control of infection and (b) for answering the question whether antigenicity-determining codon polymorphisms in IDE-encoding genes of CMV strains impact on the efficacy of CD8 T cell immunotherapy in case the donor and the recipient harbor different CMV strains.

ACS Style

Stefan Ebert; Niels Lemmermann; Doris Thomas; Angélique Renzaho; Matthias J. Reddehase; Rafaela Holtappels. Immune control in the absence of immunodominant epitopes: implications for immunotherapy of cytomegalovirus infection with antiviral CD8 T cells. Medical Microbiology and Immunology 2012, 201, 541 -550.

AMA Style

Stefan Ebert, Niels Lemmermann, Doris Thomas, Angélique Renzaho, Matthias J. Reddehase, Rafaela Holtappels. Immune control in the absence of immunodominant epitopes: implications for immunotherapy of cytomegalovirus infection with antiviral CD8 T cells. Medical Microbiology and Immunology. 2012; 201 (4):541-550.

Chicago/Turabian Style

Stefan Ebert; Niels Lemmermann; Doris Thomas; Angélique Renzaho; Matthias J. Reddehase; Rafaela Holtappels. 2012. "Immune control in the absence of immunodominant epitopes: implications for immunotherapy of cytomegalovirus infection with antiviral CD8 T cells." Medical Microbiology and Immunology 201, no. 4: 541-550.

Review
Published: 13 September 2012 in Medical Microbiology and Immunology
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Reactivation of latent cytomegalovirus (CMV) in the transient state of immunodeficiency after hematopoietic cell transplantation (HCT) is the most frequent and severe viral complication endangering leukemia therapy success. By infecting the bone marrow (BM) stroma of the transplantation recipient, CMV can directly interfere with BM repopulation by the transplanted donor-derived hematopoietic cells and thus delay immune reconstitution of the recipient. Cytopathogenic virus spread in tissues can result in CMV disease with multiple organ manifestations of which interstitial pneumonia is the most feared. There exists a ‘window of risk’ between hematoablative treatment and reconstitution of antiviral immunity after HCT, whereby timely reconstitution of antiviral CD8 T cells is a recognized positive prognostic parameter for the control of reactivated CMV infection and prevention of CMV disease. Supplementation of endogenous reconstitution by adoptive cell transfer of ‘ready-to-go’ effector and/or memory virus epitope-specific CD8 T cells is a therapeutic option to bridge the ‘window of risk.’ Preclinical research in murine models of CMV disease has been pivotal by providing ‘proof of concept’ for a benefit from CD8 T-cell therapy of HCT-associated CMV disease (reviewed in Holtappels et al. Med Microbiol Immunol 197:125–134, 2008). Here, we give an update of our previous review with focus on parameters that determine the efficacy of adoptive immunotherapy of CMV infection by antiviral CD8 T cells in the murine model.

ACS Style

Stefan Ebert; Jürgen Podlech; Dorothea Gillert-Marien; Kerstin M. Gergely; Julia K. Büttner; Annette Fink; Kirsten Freitag; Doris Thomas; Matthias Reddehase; Rafaela Holtappels. Parameters determining the efficacy of adoptive CD8 T-cell therapy of cytomegalovirus infection. Medical Microbiology and Immunology 2012, 201, 527 -539.

AMA Style

Stefan Ebert, Jürgen Podlech, Dorothea Gillert-Marien, Kerstin M. Gergely, Julia K. Büttner, Annette Fink, Kirsten Freitag, Doris Thomas, Matthias Reddehase, Rafaela Holtappels. Parameters determining the efficacy of adoptive CD8 T-cell therapy of cytomegalovirus infection. Medical Microbiology and Immunology. 2012; 201 (4):527-539.

Chicago/Turabian Style

Stefan Ebert; Jürgen Podlech; Dorothea Gillert-Marien; Kerstin M. Gergely; Julia K. Büttner; Annette Fink; Kirsten Freitag; Doris Thomas; Matthias Reddehase; Rafaela Holtappels. 2012. "Parameters determining the efficacy of adoptive CD8 T-cell therapy of cytomegalovirus infection." Medical Microbiology and Immunology 201, no. 4: 527-539.

Journal article
Published: 09 September 2012 in Medical Microbiology and Immunology
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Cytomegalovirus (CMV) disease with multiple organ manifestations is the most feared viral complication limiting the success of hematopoietic cell transplantation as a therapy of hematopoietic malignancies. A timely endogenous reconstitution of CD8 T cells controls CMV infection, and adoptive transfer of antiviral CD8 T cells is a therapeutic option to prevent CMV disease by bridging the gap between an early CMV reactivation and delayed endogenous reconstitution of protective immunity. Preclinical research in murine models has provided ‘proof of concept’ for CD8 T-cell therapy of CMV disease. Protection by CD8 T cells appears to be in conflict with the finding that CMVs encode proteins that inhibit antigen presentation to CD8 T cells by interfering with the constitutive trafficking of peptide-loaded MHC class I molecules (pMHC-I complexes) to the cell surface. Here, we have systematically explored antigen presentation in the presence of the three currently noted immune evasion proteins of murine CMV in all possible combinations and its modulation by pre-treatment of cells with interferon-gamma (IFN-γ). The data reveal improvement in antigen processing by pre-treatment with IFN-γ can almost overrule the inhibitory function of immune evasion molecules in terms of pMHC-I expression levels capable of triggering most of the specific CD8 T cells, though the intensity of stimulation did not retrieve their full functional capacity. Notably, an in vivo conditioning of host tissue cells with IFN-γ in adoptive cell transfer recipients constitutively overexpressing IFN-γ (B6-SAP-IFN-γ mice) enhanced the antiviral efficiency of CD8 T cells in this transgenic cytoimmunotherapy model.

ACS Style

Annette Fink; Niels Lemmermann; Dorothea Gillert-Marien; Doris Thomas; Kirsten Freitag; Verena Böhm; Vanessa Wilhelmi; Kurt Reifenberg; Matthias J. Reddehase; Rafaela Holtappels. 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. Medical Microbiology and Immunology 2012, 201, 513 -525.

AMA Style

Annette Fink, Niels Lemmermann, Dorothea Gillert-Marien, Doris Thomas, Kirsten Freitag, Verena Böhm, Vanessa Wilhelmi, Kurt Reifenberg, Matthias J. Reddehase, Rafaela Holtappels. 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. Medical Microbiology and Immunology. 2012; 201 (4):513-525.

Chicago/Turabian Style

Annette Fink; Niels Lemmermann; Dorothea Gillert-Marien; Doris Thomas; Kirsten Freitag; Verena Böhm; Vanessa Wilhelmi; Kurt Reifenberg; Matthias J. Reddehase; Rafaela Holtappels. 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." Medical Microbiology and Immunology 201, no. 4: 513-525.

Review
Published: 31 May 2011 in Virus Research
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Cytomegaloviruses (CMVs) co-exist with their respective host species and have evolved to avoid their elimination by the hosts’ immune effector mechanisms and to persist in a non-replicative state, known as viral latency. There is evidence to suggest that latency is nevertheless a highly dynamic condition during which episodes of viral gene desilencing, which can be viewed as incomplete reactivations, cause intermittent antigenic activity that stimulates CD8 memory-effector T cells and drives their clonal expansion. These T cells are supposed to terminate reactivation before completion of the productive viral cycle. In this view, CMVs do not “evade” their respective host's immune response but are actually held in check all the time, unless the host gets immunocompromised. Accordingly, CMV disease is typically a disease of the immunocompromised host only. Here we review current knowledge about the in vivo role of viral proteins involved in subverting the immune recognition of infected cells with focus on the CD8 T-cell response and viral interference with the MHC class-I pathway of antigenic peptide presentation. Whereas the intracellular functions of these “immune-evasion proteins” are known in molecular detail, knowledge of their in vivo role in CMV biology is only beginning to take shape. Experimental studies on the in vivo function of human CMV (hCMV) immune-evasion proteins prohibits, of course. Studying animal CMVs paradigmatically in the corresponding natural host is therefore used to identify principles from which the role of hCMV immune-evasion proteins can hopefully be inferred. Here we summarize recent insights gained primarily from the murine model.

ACS Style

Niels A.W. Lemmermann; Verena Böhm; Rafaela Holtappels; Matthias J. Reddehase. In vivo impact of cytomegalovirus evasion of CD8 T-cell immunity: Facts and thoughts based on murine models. Virus Research 2011, 157, 161 -174.

AMA Style

Niels A.W. Lemmermann, Verena Böhm, Rafaela Holtappels, Matthias J. Reddehase. In vivo impact of cytomegalovirus evasion of CD8 T-cell immunity: Facts and thoughts based on murine models. Virus Research. 2011; 157 (2):161-174.

Chicago/Turabian Style

Niels A.W. Lemmermann; Verena Böhm; Rafaela Holtappels; Matthias J. Reddehase. 2011. "In vivo impact of cytomegalovirus evasion of CD8 T-cell immunity: Facts and thoughts based on murine models." Virus Research 157, no. 2: 161-174.