B7-Mediated Costimulation of CD4 T Cells Constrains Cytomegalovirus Persistence

Arens, Ramon; Loewendorf, Andrea; Her, Min J.; Schneider-Ohrum, Kirsten; Shellam, Geoffrey; Janssen, Edith M.; Ware, Carl F.; Schoenberger, Stephen P.; Benedict, Chris A.

doi:10.1128/jvi.01839-10

Cited by 28 publications

(25 citation statements)

References 46 publications

(66 reference statements)

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“…It has been well established that costimulation via NKG2D plays an important role in shaping of the CD8 T-cell response (7,16). This function may be crucial for efficient priming of CD8 T cells by RAE-1γMCMV because MCMV down-regulates costimulatory molecules on antigen-presenting cells as does HCMV (17,18). Therefore, we investigated the capacity of RAE-1γMCMVList to prime CD8 T cells in the presence of blocking NKG2D antibodies.…”

Section: Better Priming Of Cd8 T Cells and Attenuation Of Rae-1γmcmvlmentioning

confidence: 99%

Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ

Tršan

Busche

Abram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Due to a unique pattern of CD8 T-cell response induced by cytomegaloviruses (CMVs), live attenuated CMVs are attractive candidates for vaccine vectors for a number of clinically relevant infections and tumors. NKG2D is one of the most important activating NK cell receptors that plays a role in costimulation of CD8 T cells. Here we demonstrate that the expression of CD8 T-cell epitope of Listeria monocytogenes by a recombinant mouse CMV (MCMV) expressing the NKG2D ligand retinoic acid early-inducible protein 1-gamma (RAE-1γ) dramatically enhanced the effectiveness and longevity of epitope-specific CD8 T-cell response and conferred protection against a subsequent challenge infection with Listeria monocytogenes. Unexpectedly, the attenuated growth in vivo of the CMV vector expressing RAE-1γ and its capacity to enhance specific CD8 T-cell response were preserved even in mice lacking NKG2D, implying additional immune function for RAE-1γ beyond engagement of NKG2D. Thus, vectors expressing RAE-1γ represent a promising approach in the development of CD8 T-cellbased vaccines.RAE-1 gamma | CD8 T cell vaccine | vaccine vector A lthough vaccination plays a tremendous role in protection against infectious diseases, there are many pathogens for which even the immunity acquired after natural infection does not fully protect against reinfection and disease. Therefore, vaccines which offer superior protection compared with the protection following natural infection are needed. Most of the current vaccines induce protective antibodies but often fail to confer sufficient protection. An alternative approach is to develop vaccines which are based on the induction of cellular immunity in general and cytotoxic CD8 T cells in particular (1).Cytomegaloviruses (CMVs) are excellent inducers of the CD8 T-cell response, despite having numerous immunoevasion strategies aimed at compromising antigen presentation by MHC class I molecules (2). Preferentially, CMVs induce the effector arm of memory CD8 T cells (3). This, together with a large genome allowing the insertion of multiple foreign genes, makes CMVs attractive vaccine vectors. The outstanding capacity of specific CD8 T cells induced by CMV vectors was proven by studies demonstrating the role of tissue-resident effector memory CD8 T cells in the protection against challenge infection (4, 5). The suitability of CMV as a vaccine vector was further emphasized in a recent study by Hansen et al. (6).NKG2D is a receptor expressed on several lymphocyte subsets, with a predominant role in activation of NK cells. In addition, NKG2D has a costimulatory role on CD8 T cells (7). The ligands for the NKG2D receptor are several molecules induced by stress or cell transformation. In mice, NKG2D ligands comprise the RAE-1 family (RAE-1α-e), H60 family (H60a-c), and MULT-1 proteins (8). The significance of NKG2D signaling in immune response to CMV infection is best illustrated by numerous strategies used by CMVs to evade the function of this receptor (9). We have recently shown that infection of mice wi...

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Section: Better Priming Of Cd8 T Cells and Attenuation Of Rae-1γmcmvlmentioning

confidence: 99%

Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ

Tršan

Busche

Abram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…To identify the molecular interactions that provide the help signal, we specifically focused on the role of costimulatory pathways involving the Ig superfamily member CD28 and its ligands B7.1 (CD80) and B7.2 (CD86) (here referred as B7) and the TNFR family member CD27 and its ligand CD70, because Cd80/86 Ϫ/Ϫ and Cd70 Ϫ/Ϫ mice have reduced MCMV-specific CD4 ϩ T cell responses ( Fig. 3B) (18,24). No differences were found in the MCMV-specific IgM response during acute and persistent infection in all mice devoid of B7-and/or CD70-mediated costimulatory signals (Fig.…”

Section: Mcmv-specific Igg Antibody Responses Are Dependent On Cd28/bmentioning

confidence: 99%

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Welten

Redeker

Toes

et al. 2016

J Virol

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Antibodies are implicated in long-term immunity against numerous pathogens, and because of this property, antibody induction is the basis for many vaccines. Little is known about the influence of viral persistence on the evolving antibody response. Here, we examined the characteristics of antibody responses to persistent infection by employing the prototypic betaherpesvirus family member cytomegalovirus (CMV) in experimental mouse models. During the course of infection, mouse CMV (MCMV)-specific IgM and IgG responses are elicited; however, IgG levels gradually inflate in the persistent phase of infection while IgM levels are stably maintained. Whereas CD27-CD70 interactions are dispensable, the CD28/B7 costimulatory pathway is critical for the class switching of MCMV-specific IgM-to-IgG B cell responses, which corresponds to the CD28/B7-dependent formation of CD4 ؉ T follicular helper cells (T FH ) and germinal center (GC) B cells. Furthermore, the initial viral inoculum dose dictates the height of the antibody levels during IgG antibody inflation and relates to the induction of long-lived plasma cells and memory B cells. Antibody avidity nonetheless is not altered after the establishment of viral persistence and occurs independently of the inoculum doses. However, repetitive challenge with intact viral particles, accompanied by increased GC reactivity, promotes the development of high-avidity IgG responses with neutralizing capacity. These insights can be used for the rational design of CMV-based vaccines aimed at inducing antibody responses. IMPORTANCE Antibodies provide long-term protection to different pathogens. However, how antibody responses develop during persistent virus infection is not entirely clear.Here, we characterize factors that influence the virus-specific antibody response to persistent CMV. This study describes that during persistent infection, CMV-specific IgM antibody levels are stably maintained while IgG2b and IgG2c levels gradually inflate over time. In contrast, the IgG avidity remains similar after the establishment of viral persistence. The induction of T follicular helper cells and GC B cells requires CD4 ؉ T cell help and CD28/B7 costimulation signals and is essential for the development of CMV-specific IgG antibody responses. Furthermore, neutralizing CMV-specific antibodies appear to develop late after infection, yet the neutralizing capacity can be improved upon repetitive viral challenge that is associated with increased GC reactivity. The results described here could inform the use of CMV-based vaccines and may help to understand how our immune system copes with this persistent virus.T he maintenance of long-lived humoral responses after infection and vaccination is attributed to both long-lived plasma cells that continuously produce antibodies and to memory B cells that are able to form antibody-secreting cells after reexposure (1, 2). Antibodies can protect against numerous pathogens by direct neutralization and/or by supporting effector functions of immune cells (1, ...

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“…on day 7 and then twice weekly until day 23 with 450 mg of mAb MP6-XT22. mAbs were prepared and purified as described previously (21).…”

Section: Translational Relevancementioning

confidence: 99%

Vaccine-Induced Tumor Necrosis Factor–Producing T Cells Synergize with Cisplatin to Promote Tumor Cell Death

Sluis

Duikeren

Huppelschoten

et al. 2015

Clinical Cancer Research

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Purpose: Cancer immunotherapy, such as vaccination, is an increasingly successful treatment modality, but its interaction with chemotherapy remains largely undefined. Therefore, we explored the mechanism of synergy between vaccination with synthetic long peptides (SLP) of human papillomavirus type 16 (HPV16) and cisplatin in a preclinical tumor model for HPV16.Experimental Design: SLP vaccination in this preclinical tumor model allowed the elucidation of novel mechanisms of synergy between chemo-and immunotherapy. By analyzing the tumor immune infiltrate, we focused on the local intratumoral effects of chemotherapy, vaccination, or the combination.Results: Of several chemotherapeutic agents, cisplatin synergized best with SLP vaccination in tumor eradication, without requirement for the maximum-tolerated dose (MTD). Upon SLP vaccination, tumors were highly infiltrated with HPV-specific, tumor necrosis factor-a (TNFa)-and interferon-g (IFNg)-producing T cells. Upon combined treatment, tumor cell proliferation was significantly decreased compared with single treated and untreated tumors. Furthermore, we showed that TNFa strongly enhanced cisplatin-induced apoptotic tumor cell death in a JNKdependent manner. This is consistent with upregulation of proapoptotic molecules and with enhanced cell death in vivo upon combined SLP vaccination and cisplatin treatment. In vivo neutralization of TNFa significantly reduced the antitumor responses induced by the combined treatment.Conclusion: Taken together, our data show that peptide vaccination with cisplatin treatment leads to decreased tumor cell proliferation and TNFa-induced enhanced cisplatin-mediated killing of tumor cells, together resulting in superior tumor eradication.

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B7-Mediated Costimulation of CD4 T Cells Constrains Cytomegalovirus Persistence

Cited by 28 publications

References 46 publications

Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ

Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Vaccine-Induced Tumor Necrosis Factor–Producing T Cells Synergize with Cisplatin to Promote Tumor Cell Death

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