Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung

Morabito, Kaitlyn M.; Ruckwardt, T. R.; Redwood, Alec; Moin, Syed M.; Price, David A.; Graham, Barney S.

doi:10.1038/mi.2016.48

Cited by 91 publications

(115 citation statements)

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“…Recent studies have demonstrated that T RM play a critical role in providing protection against secondary influenza virus infections [66][67][68]. Importantly, several reports have also supported a role for RSV-specific T RM in providing protection against RSV infection [12,[56][57][58]. Together, these studies establish that memory CD8 T cells provide protection against secondary RSV infection.…”

Section: Protection Against Secondary Infectionmentioning

confidence: 73%

“…1c) [38,56]. Additionally, RSV-specific T RM within the lung can also be generated by local immunization with RSV-derived antigens [12,57,58]. Overall, RSV infection induces robust activation of pulmonary CD8 T cells that form a memory population within the lung tissue following contraction in mice.…”

Section: Memory Cd8 T Cell Populations Following Rsv Infectionmentioning

confidence: 99%

“…Many studies have evaluated the capacity of memory CD8 T cells to provide protection against RSV infection by immunizing against whole RSV proteins to generate preexisting RSV-specific CD8 T cells. Viral vector-based approaches engineered to express whole RSV proteins have included recombinant baculoviruses expressing the RSV M2 protein, recombinant murine cytomegaloviruses expressing the RSV M protein, as well as virus-like particles containing both the RSV M and M2 proteins [57,58,63]. All of these immunization strategies generated RSV-specific CD8 T cell responses that significantly reduced viral titers in the lung following RSV challenge.…”

Section: Protection Against Secondary Infectionmentioning

confidence: 99%

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Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

Schmidt

Varga

2020

Cytokine

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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection and hospitalization in infants. In spite of the enormous clinical burden caused by RSV infections, there remains no efficacious RSV vaccine. CD8 T cells mediate viral clearance as well as provide protection against a secondary RSV infection. However, RSV-specific CD8 T cells may also induce immunopathology leading to exacerbated morbidity and mortality. Many of the crucial functions performed by CD8 T cells are mediated by the cytokines they produce. IFN-γ and TNF are produced by CD8 T cells following RSV infection and contribute to both the acceleration of viral clearance and the induction of immunopathology. To prevent immunopathology, regulatory mechanisms are in place within the immune system to inhibit CD8 T cell effector functions after the infection has been cleared. The actions of a variety of cytokines, including IL-10 and IL-4, play a critical role in the regulation of CD8 T cell effector activity. Herein, we review the current literature on CD8 T cell responses and the functions of the cytokines they produce following RSV infection. Additionally, we discuss the regulation of CD8 T cell activation and effector functions through the actions of various cytokines.

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Section: Protection Against Secondary Infectionmentioning

confidence: 73%

Section: Memory Cd8 T Cell Populations Following Rsv Infectionmentioning

confidence: 99%

Section: Protection Against Secondary Infectionmentioning

confidence: 99%

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Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

Schmidt

Varga

2020

Cytokine

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“…There are some antibody Fc-mediated antibody functions that could contribute to viral clearance, but in most settings they likely play an ancillary role to CD8T cells. We are learning more about the role of local mucosal induction of intraepithelial T cells and their role in viral clearance [22] and about the selection of effector cells with the optimal phenotype for accomplishing viral clearance without undue pathology [22,23], but we do not yet have enough basic knowledge to rationally design a T-cell based vaccine that can rapidly respond and clear infection without risk of disease. It is possible that knowledge will come from other vaccine development programs on HIV, malaria, or tuberculosis, and it would be valuable to include CD8 T cell immunity in a vaccine especially if one of the goals is to interrupt transmission by preventing or reducing the period of viral shedding in infected people.…”

Section: Immunitymentioning

confidence: 99%

Vaccine development for respiratory syncytial virus

Graham

2017

Current Opinion in Virology

146

114

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Respiratory syncytial virus (RSV) is an important and ubiquitous respiratory pathogen for which no vaccine is available notwithstanding more than 50 years of effort. It causes the most severe disease at the extremes of age and in settings of immunodeficiency. Although RSV is susceptible to neutralizing antibody, it has evolved multiple mechanisms of immune evasion allowing it to repeatedly infect people despite relatively little genetic diversity. Recent breakthroughs in determining the structure and antigenic content of the fusion (F) glycoprotein in its metastable untriggered prefusion form (pre-F) and the stable rearranged postfusion form (post-F) have yielded vaccine strategies that can induce potent neutralizing antibody responses and effectively boost pre-existing neutralizing activity. In parallel, novel live-attenuated and chimeric virus vaccine candidates and other novel approaches to deliver vaccine antigens have been developed. These events and activities have aroused optimism and a robust pipeline of potential vaccine products that promise to provide a means to reduce the public health burden of RSV infection.

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“…Both CD8T EM and CD8T CM subsets recirculate between the blood, the lymphoid organs, and the peripheral tissues. A special subset of memory CD8 + T cells (CD8T RM ) resides in non-lymphoid tissues such as lungs, the female reproductive tract (FRT), the skin, the brain or the small intestine [22–25]. These cells lose the capacity of recirculating, maintain themselves at the site of infection, and their phenotype and transcriptional profile differ from classical memory T cells [26].…”

Section: Introductionmentioning

confidence: 99%

Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

Zheng

Oduro

Boehme

et al. 2018

Preprint

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20Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection 21 in a high percentage of the population worldwide. CMV induces the strongest and most durable 22 CD8 + T cell response known in human clinical medicine. Due to its unique properties, the virus 23 represents a promising candidate vaccine vector for the induction of persistent cellular 24 immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) 48 but only if we administered it through the nose, to activate killer T cells that will persist in the 49 lungs close to the airways. Therefore, our data show that the subset of lung-resident killer T 50 cells is sufficient to protect against influenza. 3 51 Introduction 52 Respiratory infections caused by influenza viruses usually are associated with mild-to-53 moderate disease symptoms but are linked with high morbidity and mortality in susceptible 54 populations like the elderly, young children, patients with co-morbidities and 55 immunocompromised patients. Influenza virus causes seasonal epidemics, with typically 3 to 56 5 million cases of severe illness worldwide, according to WHO reports [1], and influenza type 57 A viruses (IAV) cause the more severe disease form. Vaccines against influenza are based on 58 the induction of adaptive immunity that targets the projected yearly epidemics. While most 59 vaccines are based on inactivated IAV formulations inducing anti-IAV IgG responses, live 60 attenuated influenza vaccines (LAIV) are also used as formulations for i.n. administration. This 61 is based on the assumption that the induction of local immunity may provide superior immune 62 protection [2, 3]. However, it remains unclear whether this protection depends on local IgA 63 responses, on cytotoxic T cell responses, or on their combined antiviral activity. Of note, 64 functional T cell responses were shown to substantially contribute to antiviral IAV immunity [4-65 6]. In particular, cytotoxic influenza-specific CD8 + T lymphocytes (CTLs) promote viral 66 clearance indirectly by secretion of pro-inflammatory cytokines such as IFNγ [7] and directly 67 by perforin/Fas-mediated killing of infected epithelial cells in the bronchoalveolar space [8]. 68 However, it remained unclear if T cell responses alone may control IAV, or if Ig responses were 69 the crucial contributor to LAIV-mediated immune protection. We considered that this question 70 could be addressed by developing a vaccine formulation that optimizes T cell responses 71 against IAV, while excluding the humoral ones. 72 CMV infection induces sustained functional T cell responses that are stronger in the long-term 73 than the immune response to any other infectious pathogen [9]. Experiments in the mouse 74 model have shown that defined CMV epitope-specific CD8 + T cells accumulate in tissues and 75 blood and are maintained at stable high levels during mouse CMV (MCMV) latency [10]. This 76 phenomenon was termed ''Memory Inflation'' [11]. While some MCMV derived peptides, as the 77 ones de...

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Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung

Cited by 91 publications

References 50 publications

Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

Vaccine development for respiratory syncytial virus

Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

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