Human Cytomegalovirus Interleukin 10 Homologs: Facing the Immune System

Poole, Emma; Neves, Tainan Cerqueira; Oliveira, Martha Trindade; Silva, Maria Cristina Carlan da

doi:10.3389/fcimb.2020.00245

Cited by 28 publications

(28 citation statements)

References 132 publications

(204 reference statements)

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“…However, a retrospect on studies of the immune response to hCMV revealed only limited evidence supportive of MI occurring in humans (23). One may speculate that missing or inhibited MI in latently infected humans may relate to the virally encoded interleukin-10, a form of which is expressed in cells latently infected with hCMV [ (93,94), reviewed in (95)]. Alternatively, in view of the broad spectrum of transcripts revealed by scRNAseq in latently infected myeloid lineage hematopoietic cells, expression of immune evasion genes interfering with the MHC/HLA class-I pathway of antigen presentation (77) might prevent MI.…”

Section: Collins-mcmillen and Goodrum To Propose An Equilibriummentioning

confidence: 99%

Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion

et al. 2021

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Acute infection with murine cytomegalovirus (mCMV) is controlled by CD8+ T cells and develops into a state of latent infection, referred to as latency, which is defined by lifelong maintenance of viral genomes but absence of infectious virus in latently infected cell types. Latency is associated with an increase in numbers of viral epitope-specific CD8+ T cells over time, a phenomenon known as “memory inflation” (MI). The “inflationary” subset of CD8+ T cells has been phenotyped as KLRG1+CD62L- effector-memory T cells (iTEM). It is agreed upon that proliferation of iTEM requires repeated episodes of antigen presentation, which implies that antigen-encoding viral genes must be transcribed during latency. Evidence for this has been provided previously for the genes encoding the MI-driving antigenic peptides IE1-YPHFMPTNL and m164-AGPPRYSRI of mCMV in the H-2d haplotype. There exist two competing hypotheses for explaining MI-driving viral transcription. The “reactivation hypothesis” proposes frequent events of productive virus reactivation from latency. Reactivation involves a coordinated gene expression cascade from immediate-early (IE) to early (E) and late phase (L) transcripts, eventually leading to assembly and release of infectious virus. In contrast, the “stochastic transcription hypothesis” proposes that viral genes become transiently de-silenced in latent viral genomes in a stochastic fashion, not following the canonical IE-E-L temporal cascade of reactivation. The reactivation hypothesis, however, is incompatible with the finding that productive virus reactivation is exceedingly rare in immunocompetent mice and observed only under conditions of compromised immunity. In addition, the reactivation hypothesis fails to explain why immune evasion genes, which are regularly expressed during reactivation in the same cells in which epitope-encoding genes are expressed, do not prevent antigen presentation and thus MI. Here we show that IE, E, and L genes are transcribed during latency, though stochastically, not following the IE-E-L temporal cascade. Importantly, transcripts that encode MI-driving antigenic peptides rarely coincide with those that encode immune evasion proteins. As immune evasion can operate only in cis, that is, in a cell that simultaneously expresses antigenic peptides, the stochastic transcription hypothesis explains why immune evasion is not operative in latently infected cells and, therefore, does not interfere with MI.

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Section: Collins-mcmillen and Goodrum To Propose An Equilibriummentioning

confidence: 99%

Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion

et al. 2021

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“…After clearance of productive CMV infection, a latent infection, briefly referred to as “latency”, is established, which is defined by the presence of replication-competent viral genomes that are silenced at loci critical for completion of the viral replicative cycle so that infectious progeny is not produced [ 14 , 15 ]. However, there is increasing evidence for viral gene expression during latency that does not follow the canonical temporal cascade of gene expression during productive infection [ 16 ] and that can impact the cellular secretome to create a latency-modulated microenvironment [ 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Localization of Viral Epitope-Specific CD8 T Cells during Cytomegalovirus Latency in the Lungs and Recruitment to Lung Parenchyma by Airway Challenge Infection

Blaum

Lukas

Reddehase

et al. 2021

Life

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Interstitial pneumonia is a life-threatening clinical manifestation of cytomegalovirus infection in recipients of hematopoietic cell transplantation (HCT). The mouse model of experimental HCT and infection with murine cytomegalovirus revealed that reconstitution of virus-specific CD8+ T cells is critical for resolving productive lung infection. CD8+ T-cell infiltrates persisted in the lungs after the establishment of latent infection. A subset defined by the phenotype KLRG1+CD62L− expanded over time, a phenomenon known as memory inflation (MI). Here we studied the localization of these inflationary T effector-memory cells (iTEM) by comparing their frequencies in the intravascular and transmigration compartments, the IVC and TMC, respectively, with their frequency in the extravascular compartment (EVC), the alveolar epithelium. Frequencies of viral epitope-specific iTEM were comparable in the IVC and TMC but were reduced in the EVC, corresponding to an increase in KLRG1−CD62L− conventional T effector-memory cells (cTEM) and a decrease in functional IFNγ+CD8+ T cells. As maintained expression of KLRG1 requires stimulation by antigen, we conclude that iTEM lose KLRG1 and convert to cTEM after transmigration into the EVC because pneumocytes are not latently infected and, therefore, do not express antigens. Accordingly, antigen re-expression upon airway challenge infection recruited virus-specific CD8+ T cells to TMC and EVC.

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“…Like the human IL-10, cmvIL10 has a broad range of immunomodulatory functions, particularly on myeloid cells, which also serve as a latent reservoir for the virus. It has been reported to inhibit the maturation and function of DCs and down-regulate the expression of MHC Class II on myeloid cells, all of which are detrimental to antigen presentation [174,175]. Reactivation of CMV can lead to a state of chronic inflammation, postulated to lead to "exhaustion" of various immune cell populations [176].…”

Section: Geneticsmentioning

confidence: 99%

Antibody Responsiveness to Influenza: What Drives It?

Lin

Liang

et al. 2021

Viruses

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The induction of a specific antibody response has long been accepted as a serological hallmark of recent infection or antigen exposure. Much of our understanding of the influenza antibody response has been derived from studying antibodies that target the hemagglutinin (HA) protein. However, growing evidence points to limitations associated with this approach. In this review, we aim to highlight the issue of antibody non-responsiveness after influenza virus infection and vaccination. We will then provide an overview of the major factors known to influence antibody responsiveness to influenza after infection and vaccination. We discuss the biological factors such as age, sex, influence of prior immunity, genetics, and some chronic infections that may affect the induction of influenza antibody responses. We also discuss the technical factors, such as assay choices, strain variations, and viral properties that may influence the sensitivity of the assays used to measure influenza antibodies. Understanding these factors will hopefully provide a more comprehensive picture of what influenza immunogenicity and protection means, which will be important in our effort to improve influenza vaccines.

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Human Cytomegalovirus Interleukin 10 Homologs: Facing the Immune System

Cited by 28 publications

References 132 publications

Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion

Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion

Localization of Viral Epitope-Specific CD8 T Cells during Cytomegalovirus Latency in the Lungs and Recruitment to Lung Parenchyma by Airway Challenge Infection

Antibody Responsiveness to Influenza: What Drives It?

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