Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection

Gibson, Laura; Barysauskas, Constance M.; McManus, Margaret; Dooley, Sheryl; Lilleri, Daniele; Fisher, Donna; Srivastava, Tumul; Diamond, Don J.; Luzuriaga, Katherine

doi:10.1007/s10875-015-0139-3

Cited by 26 publications

(23 citation statements)

References 76 publications

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“…Low levels of the cytolytic enzymes granzymes A and B and MIP-1␤ were also detected. The polyfunctional CD4 ϩ T cell responses observed are important, as polyfunctional CD4 ϩ T cells have been shown to be better effector cells (50) and reduced frequencies of polyfunctional CMV-specific CD4 ϩ T cells are associated with the occurrence of congenital CMV infections (70). However, these assays still just measure effector mechanisms and do not give any indication whether the T cells could mediate direct antiviral activity.…”

Section: Discussionmentioning

confidence: 99%

“…CD4 ϩ T cells specific to HCMV have a cytotoxic capability and secrete MIP-1␤ and IFN-␥, which are known to be essential to control viral replication (13,20,70) and can control viral dissemination in vitro. Previous studies focusing solely on T cell responses to limited HCMV ORF-encoded proteins or inactive viral lysate in the immune response of older people (71) may have resulted in a perspective on understanding the etiology of the CMV infection and diseases in healthy older people that was too narrow.…”

Section: Discussionmentioning

confidence: 99%

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Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Jackson

Sedikides

Mason

et al. 2017

J Virol

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Human cytomegalovirus (HCMV) infection and periodic reactivation are generally well controlled by the HCMV-specific T cell response in healthy people. While the CD8 ϩ T cell response to HCMV has been extensively studied, the HCMVspecific CD4 ϩ T cell effector response is not as well understood, especially in the context of direct interactions with HCMV-infected cells. We screened the gamma interferon (IFN-␥) and interleukin-10 (IL-10) responses to 6 HCMV peptide pools (pp65, pp71, IE1, IE2, gB, and US3, selected because they were the peptides most frequently responded to in our previous studies) in 84 donors aged 23 to 74 years. The HCMV-specific CD4 ϩ T cell response to pp65, IE1, IE2, and gB was predominantly Th1 biased, with neither the loss nor the accumulation of these responses occurring with increasing age. A larger proportion of donors produced an IL-10 response to pp71 and US3, but the IFN-␥ response was still dominant. CD4 ϩ T cells specific to the HCMV proteins studied were predominantly effector memory cells and produced both cytotoxic (CD107a expression) and cytokine (macrophage inflammatory protein 1␤ secretion) effector responses. Importantly, when we measured the CD4 ϩ T cell response to cytomegalovirus (CMV)-infected dendritic cells in vitro, we observed that the CD4 ϩ T cells produced a range of cytotoxic and secretory effector functions, despite the presence of CMV-encoded immune evasion molecules. CD4 ϩ T cell responses to HCMV-infected dendritic cells were sufficient to control the dissemination of virus in an in vitro assay. Together, the results show that HCMV-specific CD4 ϩ T cell responses, even those from elderly individuals, are highly functional and are directly antiviral.IMPORTANCE Human cytomegalovirus (HCMV) infection is carried for a lifetime and in healthy people is kept under control by the immune system. HCMV has evolved many mechanisms to evade the immune response, possibly explaining why the virus is never eliminated during the host's lifetime. The dysfunction of immune cells associated with the long-term carriage of HCMV has been linked with poor responses to new pathogens and vaccines when people are older. In this study, we investigated the response of a subset of immune cells (CD4 ϩ T cells) to HCMV proteins in healthy donors of all ages, and we demonstrate that the functionality of CD4 ϩ T cells is maintained. We also show that CD4 ϩ T cells produce effector functions in response to HCMV-infected cells and can prevent virus spread. Our work demonstrates that these HCMV-specific immune cells retain many important functions and help to prevent deleterious HCMV disease in healthy older people.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Jackson

Sedikides

Mason

et al. 2017

J Virol

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“…Longitudinal samples were collected from young infants with ages ranging from 1 wk to 2.5 y. Prior reports from our group (63)(64)(65) and others (66) have shown that HCMV-specific CD8 + T-cell responses with similar antigen specificity, phenotype, and functional profiles as adults are detectable in infants with congenital CMV infection, even during gestation. Other studies have shown that infants can generate HIV-specific CD8 + T-cell responses that exert selective pressure and contribute to the evolution of viral quasi-species over the first year of life (67).…”

Section: Discussionmentioning

confidence: 99%

Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

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

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112

129

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Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.human cytomegalovirus | HCMV | congenital CMV | virology | evolution

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“…During neonatal colonization, lung microbiota exposure induces PD‐L1 expression, the ligand for inhibitory receptor PD‐1, on CD11b + conventional DCs presumably promoting tolerance to colonization . Furthermore, CMV infected human infant's express high levels of PD‐1 and an exhaustion phenotype on T cells . Late‐onset sepsis (>48 h postbirth) is associated with increased expression of CEACAM1 + CD4 + T cells, as well as increased levels of soluble CEACAM1…”

Section: Tcr Inhibitory Moleculesmentioning

confidence: 99%

Dissecting the defects in the neonatal CD8+ T-cell response

Fike

Kumova

Carey

2019

Journal of Leukocyte Biology

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The neonatal period presents a complex scenario where the threshold of reactivity toward colonizing microbiota, maternal antigens, autoantigens, and pathogens must be carefully moderated and balanced. CD8+ T cells are critical for the response against intracellular bacteria and viruses, but this immune compartment maintains altered function relative to adult counterparts because of the unique challenges which infants face. Here, we review our current understanding of the factors which may promote the attenuation and altered function of the neonatal CD8+ T‐cell response and potential avenues for future study. Specifically, we have focused on the neonatal CD8+ T‐cell ontogeny, memory formation, TCR structure and repertoire, TCR inhibitory receptors, and the clinical implications of altered neonatal CD8+ T‐cell function. Special emphasis has been placed on examining the response of preterm neonates relative to term neonates and adults.

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Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection

Cited by 26 publications

References 76 publications

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Limits and patterns of cytomegalovirus genomic diversity in humans

Dissecting the defects in the neonatal CD8+ T-cell response

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Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection

Cited by 26 publications

References 76 publications

Human Cytomegalovirus (HCMV)-Specific CD4 + T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Human Cytomegalovirus (HCMV)-Specific CD4 + T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Limits and patterns of cytomegalovirus genomic diversity in humans

Dissecting the defects in the neonatal CD8+ T-cell response

Contact Info

Product

Resources

About

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro