The Context of Gene Expression Defines the Immunodominance Hierarchy of Cytomegalovirus Antigens

Dekhtiarenko, Iryna; Jarvis, Michael A.; Ruzsics, Zsolt; Čičin‐Šain, Luka

doi:10.4049/jimmunol.1203173

Cited by 64 publications

(102 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, this mechanism does not explain the published DQ6-restricted pp65 41–55 LLQTGIHVRVSQPSL epitope-induced inflation (11), suggesting that multiple factors underlie inflation. Differential gene expression patterns (70), and the presence of higher avidity TCRs specific for DYS might also play some role. It is important to note that cytotoxic CD4 + T cells in general are elevated in HIV infection (71).…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus (CMV) Epitope–Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects

Abana

Pilkinton

Gaudieri

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Select CMV epitopes drive life-long CD8+ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4+ T cells specific for human CMV (HCMV) are elevated in HIV+ HCMV+ subjects. To determine whether HCMV epitope-specific CD4+ T cell memory inflation occurs during HIV infection, we used HLA-DR7 tetramers loaded with the glycoprotein-B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in co-infected, HLA-DR7+ long-term non-progressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared to those from a HIV− HCMV+ HLA-DR7+ cohort, or to HLA-DR7-restricted CD4+ T cells from the HIV co-infected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, Epstein-Barr virus nuclear antigen 2 or HIV gag protein. Inflated DYS-specific CD4+ T cells comprised effector memory or effector memory-RA+ subsets with restricted TCR-beta usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near monoclonal TCR in a Jurkat cell transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme-B, CX3CR1, CD38 or HLA-DR, but were less often CD38+HLA-DR+ co-expressing. The inflation mechanism did not involve apoptosis suppression, increased proliferation or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes such as DYS drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus (CMV) Epitope–Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects

Abana

Pilkinton

Gaudieri

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The bacterial artificial chromosome (BAC)-derived wildtype MCMV (MCMV WT) (35) and MCMV r strains (34) have been described previously. To generate the MCMV IE2SL-MIEP mutant, the sequence encoding the SSIEFARL peptide was inserted at the 3= end of the ie2 gene, as described before (36), whereupon the full-length major immediate early promoter (MIEP) sequence was inserted into this mutant using a previously described construct and insertion site (34). Viral growth of the new mutant was assessed by infecting NIH 3T3 cells with MCMV IE2SL-MIEP or MCMV WT at an MOI of 0.1 as described elsewhere (34), and no growth impairment was observed.…”

Section: Micementioning

confidence: 99%

“…We used the new LSEC line LSEC B6 and generated a recombinant MCMV (MCMV IE2SL-MIEP ) expressing two fluorescent proteins under the control of the full-length major immediate early promoter-enhancer, akin to the previously published MCMV r (34). The mutant also encoded the K b -restricted peptide SSIEFARL as a C-terminal tag on the IE2 viral gene, because this expression context results in robust SSIEFARL-specific CD8 responses upon infection with recombinant MCMV (36). More importantly, this allowed us to use SSIEFARL-specific CD8 ϩ T cells derived from T cell receptor (TCR)-transgenic gBT-I mice (33), recognizing virus-infected cells in coculture experiments.…”

Section: Myeloid Dendritic Cells Repress MCMV Immediate Early Gene Exmentioning

confidence: 99%

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

Holzki

Dağ

Dekhtiarenko

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Cytomegalovirus (CMV) is a ubiquitous beta-herpesvirus whose reactivation from latency is a major cause of morbidity and mortality in immunocompromised hosts. Mouse CMV (MCMV) is a well-established model virus to study virus-host interactions. We showed in this study that the CD8-independent antiviral function of myeloid dendritic cells (mDC) is biologically relevant for the inhibition of MCMV replication in vivo and in vitro. In vivo ablation of CD11c ؉ DC resulted in higher viral titers and increased susceptibility to MCMV infection in the first 3 days postinfection. We developed in vitro coculture systems in which we cocultivated MCMV-infected endothelial cells or fibroblasts with T cell subsets and/or dendritic cells. H uman cytomegalovirus (HCMV) is a betaherpesvirus which establishes a lifelong latent infection in immunocompetenthosts. Latent HCMV is present in the majority of people worldwide, but the primary infection is usually asymptomatic. The primary infection is well contained by the immune cells, such as natural killer (NK) cells and T cells, which also prevent viral reactivation from latency (1, 2).Their activation depends on cross talk with dendritic cells (DC) (3, 4), and this interaction plays an important role in CMV control (5-7). The direct effect of DC on viral replication remains, however, unclear.In immunocompromised hosts, like AIDS patients or people undergoing transplantation, the virus cannot be contained, and its reactivation from latency has been associated with severe disease (8). Therefore, to develop new therapeutic approaches against CMV disease, it is exceedingly important to understand the immune mechanisms that drive the virus into latency.Murine cytomegalovirus (MCMV) is a natural pathogen of the mouse. It shows numerous analogies in latency and reactivation to the human virus, and its genome displays substantial similarity to the HCMV one (9). Therefore, MCMV is a widely used model for CMV infection and immunity (10)(11)(12).During primary infection, MCMV infects various different cell types, such as macrophages and DC but also nonhematopoietic cells, including endothelial and epithelial cells (13). On the other hand, the establishment of latency appears to be restricted to certain cell types. Latent HCMV was found in blood monocytes and in progenitor cells of the myeloid lineage (14-19), whereas liver sinusoidal endothelial cells (LSEC) were shown to be a site of MCMV latency and reactivation (20, 21), although myeloid cells might also present a latent reservoir in the mouse (22, 23).

show abstract

“…The gB-8p peptide was inserted into the MCMV genome at the 3′ end of the MCMV ie2 gene, as previously described (27). MCMV-gB viral stocks were propagated and quantified on M2-10B4 cells (CRL-1972, ATCC).…”

Section: Methodsmentioning

confidence: 99%

The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection

Venturi

Nzingha

Amos

et al. 2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Cytomegalovirus (CMV) is the most common congenital infection in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment and sensorineural hearing loss. Previous reports have shown that CD8+ T cells are required to control viral replication and significant numbers of CMV-specific CD8+ T cells persist in the brain even after the initial infection has been cleared. However, the dynamics of CD8+ T cells in the brain during latency remains largely undefined. In this report, we used T cell receptor (TCR) sequencing to track the development and maintenance of neonatal clonotypes in the brain and spleen of mice during chronic infection. Given the discontinuous nature of tissue resident memory CD8+ T cells, we hypothesized that neonatal TCR clonotypes would be ‘locked-in’ the brain and persist into adulthood. Surprisingly, we found that the antigen-specific T cell repertoire in neonatal-infected mice diversified during persistent infection in both the brain and spleen, while maintaining substantial similarity between the CD8+ T cell populations in the brain and spleen in both early and late infection. However, despite the diversification of, and potential interchange between, the spleen and brain antigen-specific T cell repertoires, we observed that germline-encoded TCR clonotypes, characteristic of neonatal infection, persisted in the brain, albeit sometimes in low abundance. These results provide valuable insights into the evolution of CD8+ T cell repertoires following neonatal CMV infection and thus have important implications for the development of therapeutic strategies to control CMV in early life.

show abstract

The Context of Gene Expression Defines the Immunodominance Hierarchy of Cytomegalovirus Antigens

Cited by 64 publications

References 34 publications

Cytomegalovirus (CMV) Epitope–Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects

Cytomegalovirus (CMV) Epitope–Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection

Contact Info

Product

Resources

About