Wild-type coxsackievirus infection dramatically alters the abundance, heterogeneity, and immunostimulatory capacity of conventional dendritic cells in vivo

Kemball, Christopher C.; Flynn, Claudia T.; Hosking, Martin P.; Botten, Jason; Whitton, J. Lindsay

doi:10.1016/j.virol.2012.04.005

Cited by 14 publications

(13 citation statements)

References 90 publications

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“…We have not yet elucidated the immune mechanisms responsible for viral clearance from the heart in our juvenile mouse model. However, the limited CD3 staining in the heart observed at 2 and 77 days is consistent with previous studies demonstrating a lack of functional antiviral T cells following CVB3 infection [40], [41], and suggests that the type I interferon response may ultimately be responsible for controlling the viral infection [42]. We observed that after CVB3 exposure in vivo , CPCs showed a strong tendency to differentiate into vascular cells.…”

Section: Discussionsupporting

confidence: 92%

The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

et al. 2014

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Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

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Section: Discussionsupporting

confidence: 92%

The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

et al. 2014

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“…As previously described (3, 18) small (~5mg) pieces of spleen were harvested and stored in RNA later (Qiagen). RNA was isolated using RNeasy mini (Qiagen) with on-column DNA digestion according to manufacturer instructions.…”

Section: Methodsmentioning

confidence: 99%

Antigen-Specific Naive CD8+ T Cells Produce a Single Pulse of IFN-γ In Vivo within Hours of Infection, but without Antiviral Effect

Hosking

Flynn

Whitton

2014

The Journal of Immunology

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In vitro studies have shown that naïve CD8+ T cells are unable to express most of their effector proteins until after at least one round of cell division has taken place. We have re-assessed this issue in vivo, and find that naïve CD8+ T cells mount antigen-specific responses within hours of infection, before proliferation has commenced. Newly-activated naïve antigen specific CD8+ T cells produce a rapid pulse of IFNγ in vivo and begin to accumulate granzyme B and perforin. Later, in vivo cytolytic activity is detectable, coincident with the initiation of cell division. Despite the rapid development of these functional attributes, no antiviral effect was observed early during infection, even when the cells are present in numbers similar to those of virus-specific memory cells. The evolutionary reason for the pulse of IFNγ synthesis by naïve T cells is uncertain, but the lack of antiviral impact suggests that it may be regulatory.

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“…Reaction conditions were as follows: 25°C for 10 min, 48°C for 30 min, and 95°C for 5 min. Real time PCR was performed as described (10) using Taqman Universal PCR master mix (Applied Biosystems) with the following primers and probe: Forward primer (900nM) 5′-CGCTGGCCTGGGTGAAT-3′, Reverse primer (900nM) 5′-ATGGGAAAACACAACAATTGATCTC-3′ (Valuegene), and probe (200nM) 6FAM-CTGCAGGTTTCTCGC-MGBNFQ (Applied Biosystems). Reaction conditions were: 95°C for 10 min and 40 cycles of 95°C for 15 sec and 60°C for 1 min.…”

Section: Methodsmentioning

confidence: 99%

CD8+ Memory T Cells Appear Exhausted within Hours of Acute Virus Infection

Hosking

Flynn

Botten

et al. 2013

The Journal of Immunology

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CD8+ memory T cells are abundant, and are activated in a near-synchronous manner by infection, thereby providing a unique opportunity to evaluate the coordinate functional and phenotypic changes that occur in vivo within hours of viral challenge. Using two disparate virus challenges of mice, we show that splenic CD8+ memory T cells rapidly produced IFNγ in vivo, but, within 18–24 hours, IFNγ synthesis was terminated, and remained undetectable for ≥48 hours. A similar on/off response was observed in CD8+ memory T cells in the peritoneal cavity. Cessation of IFNγ production in vivo occurred despite the continued presence of immunostimulatory viral antigen, indicating that the initial IFNγ response had been actively down-regulated and that the cells had been rendered refractory to subsequent in vivo antigen contact. Down-regulation of IFNγ synthesis was accompanied by the upregulation of inhibitory receptor expression on the T cells, and ex vivo analyses using synthetic peptides revealed a concurrent hierarchical loss of cytokine responsiveness (IL-2, then TNF, then IFNγ) taking place during the first 24 hours following antigen contact. Thus, within hours of virus challenge, CD8+ memory T cells display the standard hallmarks of T cell exhaustion, a phenotype that has previously been associated only with chronic diseases, and that is generally viewed as a gradually-developing and pathological change in T cell function. Our data suggest that, instead, the “exhaustion” phenotype is a rapid and normal physiological T cell response.

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Wild-type coxsackievirus infection dramatically alters the abundance, heterogeneity, and immunostimulatory capacity of conventional dendritic cells in vivo

Cited by 14 publications

References 90 publications

The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

Antigen-Specific Naive CD8+ T Cells Produce a Single Pulse of IFN-γ In Vivo within Hours of Infection, but without Antiviral Effect

CD8+ Memory T Cells Appear Exhausted within Hours of Acute Virus Infection

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