Programmed Death-1 Impairs Secondary Effector Lung CD8+ T Cells during Respiratory Virus Reinfection

Erickson, John J.; Rogers, Meredith C.; Hastings, Andrew K.; Williams, John V.

doi:10.4049/jimmunol.1302208

Cited by 36 publications

(63 citation statements)

References 52 publications

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“…153 Similarly to it is observed in B7tg mice, blockade of PD-1 in mMT mice restored lung CD8 C T cell effector functions (i.e., degranulation and cytokine production) and enhanced viral clearance. 153 In other studies, immunization of mMT mice with virus-like particles encoding the hMPV F and M proteins, generates hMPV F-specific and M-specific CD8 C T cells in lungs, but their function is impaired, as inhibitory receptors are upregulated on these cells, similar to what is seen in WT C57BL/6 mice under a second hMPV infection. 149 On the other hand, the depletion of CD8 C T cells in hMPV-infected BALB/c mice resulted in a lower lung pathological score, although to a lesser degree than depletion of only CD4 C T cells.…”

Section: Cd8mentioning

confidence: 87%

“…152 In other studies, an impairment of lung hMPV-specific memory CD8 C T cells was observed in mMT mice, which lack B-cells and are used as a model for hMPV reinfection, which suggest the importance of memory CD8 C T cells in viral clearance during a second infection. 153 Specifically, during reinfection, CD8 C T cells had upregulated several inhibitory receptors, including PD-1. 153 Similarly to it is observed in B7tg mice, blockade of PD-1 in mMT mice restored lung CD8 C T cell effector functions (i.e., degranulation and cytokine production) and enhanced viral clearance.…”

Section: Cd8mentioning

confidence: 99%

“…153 Specifically, during reinfection, CD8 C T cells had upregulated several inhibitory receptors, including PD-1. 153 Similarly to it is observed in B7tg mice, blockade of PD-1 in mMT mice restored lung CD8 C T cell effector functions (i.e., degranulation and cytokine production) and enhanced viral clearance. 153 In other studies, immunization of mMT mice with virus-like particles encoding the hMPV F and M proteins, generates hMPV F-specific and M-specific CD8 C T cells in lungs, but their function is impaired, as inhibitory receptors are upregulated on these cells, similar to what is seen in WT C57BL/6 mice under a second hMPV infection.…”

Section: Cd8mentioning

confidence: 99%

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Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

et al. 2016

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Human Respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are the two major etiological viral agents of lower respiratory tract diseases, affecting mainly infants, young children and the elderly. Although the infection of both viruses trigger an antiviral immune response that mediate viral clearance and disease resolution in immunocompetent individuals, the promotion of long-term immunity appears to be deficient and reinfection are common throughout life. A possible explanation for this phenomenon is that hRSV and hMPV, can induce aberrant T cell responses, which leads to exacerbated lung inflammation and poor T and B cell memory immunity. The modulation of immune response exerted by both viruses include different strategies such as, impairment of immunological synapse mediated by viral proteins or soluble factors, and the induction of pro-inflammatory cytokines by epithelial cells, among others. All these viral strategies contribute to the alteration of the adaptive immunity in order to increase the susceptibility to reinfections.In this review, we discuss current research related to the mechanisms underlying the impairment of T and B cell immune responses induced by hRSV and hMPV infection. In addition, we described the role each virulence factor involved in immune modulation caused by these viruses.

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Section: Cd8mentioning

confidence: 87%

Section: Cd8mentioning

confidence: 99%

Section: Cd8mentioning

confidence: 99%

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Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

et al. 2016

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“…This model is well established as a good one for viral replication and the development and assessment of adaptive immune responses (15,76), but other groups studying HMPV use the BALB/c mouse model, and some differences do exist (77,78). Specifically related to T cell polarization, ϩ MHC class II high CD11b ϩ DCs (B, E), CD11c ϩ MHC class II high CD11b Ϫ DCs (C, E), and CD11c Ϫ MHC class II mid CD11b ϩ interstitial macrophages (D, E).…”

Section: Both Wt and Ifnarmentioning

confidence: 99%

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Hastings

Erickson

Schuster

et al. 2015

J Virol

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Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR ؊/؊ ) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8 ؉ T cell response. HMPV-infected IFNAR ؊/؊ mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR ؊/؊ mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8؉ T cells of IFNAR ؊/؊ mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8 ؉ T cells of IFNAR ؊/؊ mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1 low dendritic cells (DCs), but not PD-L1 high alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8 ؉ T cell impairment. IMPORTANCE Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8 ؉ T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8؉ T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8 ؉ T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8 ؉ T cell impairment. H uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory infection (LRI), with infants and elderly and immunocompromised persons at the highest risk of severe complications from viral infection (1-9). No licensed therapeutics or vaccines exist to combat or prevent HMPV infection. Nearly all individuals have been exposed to HMPV by the age of 5 years (10, 11). Infection with this virus results in a neutralizing antibody (n...

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“…We previously reported that HMPV lower respiratory tract infection led to impairment of lung T CD8 function through PD-1 signaling, while splenic T CD8 s remained functional and PD-1 low (34). The memory T CD8 response to HMPV was also impaired via PD-1 signaling (35). Blockade or genetic ablation of PD-1 enhanced lung T CD8 function in vitro and viral clearance in vivo during both primary and secondary infections, suggesting that a pulmonary T CD8 memory response with low PD-1 expression might be correlated with enhanced protection.…”

mentioning

confidence: 93%

Lung CD8⁺T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8⁺T Cells

Wen

Schuster

Gilchuk

et al. 2015

J Virol

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Human metapneumovirus (HMPV) is a major cause of respiratory disease in infants, the elderly, and immunocompromised individuals worldwide. There is currently no licensed HMPV vaccine. Virus-like particles (VLPs) are an attractive vaccine candidate because they are noninfectious and elicit a neutralizing antibody response. However, studies show that serum neutralizing antibodies are insufficient for complete protection against reinfection and that adaptive T cell immunity is important for viral clearance. HMPV and other respiratory viruses induce lung CD8 ؉ T cell (T CD8 ) impairment, mediated by programmed death 1 (PD-1). In this study, we generated HMPV VLPs by expressing the fusion and matrix proteins in mammalian cells and tested whether VLP immunization induces functional HMPV-specific T CD8 responses in mice. C57BL/6 mice vaccinated twice with VLPs and subsequently challenged with HMPV were protected from lung viral replication for at least 20 weeks postimmunization. A single VLP dose elicited F-and M-specific lung T CD8 s with higher function and lower expression of PD-1 and other inhibitory receptors than T CD8 s from HMPV-infected mice. However, after HMPV challenge, lung T CD8 s from VLP-vaccinated mice exhibited inhibitory receptor expression and functional impairment similar to those of mice experiencing secondary infection. HMPV challenge of VLP-immunized MT mice also elicited a large percentage of impaired lung T CD8 s, similar to mice experiencing secondary infection. Together, these results indicate that VLPs are a promising vaccine candidate but do not prevent lung T CD8 impairment upon HMPV challenge. IMPORTANCEHuman metapneumovirus (HMPV) is a leading cause of acute respiratory disease for which there is no licensed vaccine. Viruslike particles (VLPs) are an attractive vaccine candidate and induce antibodies, but T cell responses are less defined. Moreover, HMPV and other respiratory viruses induce lung CD8 ؉ T cell (T CD8 ) impairment mediated by programmed death 1 (PD-1). In this study, HMPV VLPs containing viral fusion and matrix proteins elicited epitope-specific T CD8 s that were functional with low PD-1 expression. Two VLP doses conferred sterilizing immunity in C57BL/6 mice and facilitated HMPV clearance in antibodydeficient MT mice without enhancing lung pathology. However, regardless of whether responding lung T CD8 s had previously encountered HMPV antigens in the context of VLPs or virus, similar proportions were impaired and expressed comparable levels of PD-1 upon viral challenge. These results suggest that VLPs are a promising vaccine candidate but do not prevent lung T CD8 impairment upon HMPV challenge. in 2001 (1, 2). The virus is a major cause of acute respiratory morbidity and mortality in infants, older adults, and immunocompromised individuals, although serological studies indicate that almost all humans have been infected by 5 years of age (2, 3). There are four subtypes of HMPV classified by genotype: A1, A2, B1, and B2 (4). The fusion (F) protein, which mediates ...

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Programmed Death-1 Impairs Secondary Effector Lung CD8+ T Cells during Respiratory Virus Reinfection

Cited by 36 publications

References 52 publications

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Lung CD8⁺T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8⁺T Cells

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Programmed Death-1 Impairs Secondary Effector Lung CD8+ T Cells during Respiratory Virus Reinfection

Cited by 36 publications

References 52 publications

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Lung CD8+T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8+T Cells

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Lung CD8⁺T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8⁺T Cells