CD4 T cells control development and maintenance of brain-resident CD8 T cells during polyomavirus infection

Mockus, Taryn E; Shwetank, ..; Lauver, Matthew D; Ren, Heather M.; Netherby, Colleen S.; Salameh, T.; Imamura, Yuka; Yue, Feng Yun; Broach, James R.; Lukacher, Aron E.

doi:10.1371/journal.ppat.1007365

Cited by 32 publications

(53 citation statements)

References 96 publications

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“…2D). Recognizing that differences in hydrocephalus can reflect deficits in endothelial barrier integrity and that IFNs have been shown to regulate BBB integrity in other mouse-viral CNS infection models (27,35,36), we next quantified permeability of the BBB by extravasation of intraperitoneally (i.p.) administered sodium fluorescein dye into the brain at day 9 p.i.…”

Section: Resultsmentioning

confidence: 99%

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CD8 T Cells and STAT1 Signaling Are Essential Codeterminants in Protection from Polyomavirus Encephalopathy

Mockus

Netherby

Atkins

et al. 2020

J Virol

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JC polyomavirus (JCPyV), a human-specific virus, causes the aggressive brain-demyelinating disease progressive multifocal leukoencephalopathy (PML) in individuals with depressed immune status. The increasing incidence of PML in patients receiving immunotherapeutic and chemotherapeutic agents creates a pressing clinical need to define biomarkers to stratify PML risk and develop anti-JCPyV interventions. Mouse polyomavirus (MuPyV) CNS infection causes encephalopathology and may provide insight into JCPyV-PML pathogenesis. Type I, II, and III interferons (IFNs), which all signal via the STAT1 transcription factor, mediate innate and adaptive immune defense against a variety of viral infections. We previously reported that type I and II IFNs control MuPyV infection in non-central nervous system (CNS) organs, but their relative contributions to MuPyV control in the brain remain unknown. To this end, mice deficient in type I, II, or III IFN receptors or STAT1 were infected intracerebrally with MuPyV. We found that STAT1, but not type I, II, or III IFNs, mediated viral control during acute and persistent MuPyV encephalitis. Mice deficient in STAT1 also developed severe hydrocephalus, blood-brain barrier permeability, and increased brain infiltration by myeloid cells. CD8 T cell deficiency alone did not increase MuPyV infection and pathology in the brain. In the absence of STAT1 signaling, however, depletion of CD8 T cells resulted in lytic infection of the choroid plexus and ependymal lining, marked meningitis, and 100% mortality within 2 weeks postinfection. Collectively, these findings indicate that STAT1 signaling and CD8 T cells cocontribute to controlling MuPyV infection in the brain and CNS injury. IMPORTANCE A comprehensive understanding of JCPyV-induced PML pathogenesis is needed to define determinants that predispose patients to PML, a goal whose urgency is heightened by the lack of anti-JCPyV agents. A handicap to achieving this goal is the lack of a tractable animal model to study PML pathogenesis. Using intracerebral inoculation with MuPyV, we found that MuPyV encephalitis in wild-type mice causes an encephalopathy, which is markedly exacerbated in mice deficient in STAT1, a molecule involved in transducing signals from type I, II, and III IFN receptors. CD8 T cell deficiency compounded the severity of MuPyV neuropathology and resulted in dramatically elevated virus levels in the CNS. These findings demonstrate that STAT1 signaling and CD8 T cells concomitantly act to mitigate MuPyV-encephalopathy and control viral infection.

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Section: Resultsmentioning

confidence: 99%

“…Blood-brain barrier permeability assay. BBB permeability was measured as described previously (27,36).…”

Section: Methodsmentioning

confidence: 99%

CD8 T Cells and STAT1 Signaling Are Essential Codeterminants in Protection from Polyomavirus Encephalopathy

Mockus

Netherby

Atkins

et al. 2020

J Virol

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“…As stated above, the CD103 integrin is generally thought to tether T RM to epithelial cells, but there is little evidence for E-cadherin expression in the CNS [42]. Furthermore, CD8 T cells isolated from brains of mice infected with T. gondii vary in CD103 expression, with no overt difference in their location or function between CD103 + and CD103 − populations [7,42]. CD103 expression has been linked with T. gondii-specific CD8 bT RM that have higher TCR affinities, suggesting that its expression is related to high TCR stimulation during activation [66], but this remains correlative.…”

Section: Cd103 In the Cnsmentioning

confidence: 99%

“…Multiple lines of evidence document the importance of CD4 T cell help in directing the differentiation of naïve CD8 T cells [5][6][7]9,48,76]. During priming (the accumulation of signals during the initial activation of CD8 T cells when they encounter their cognate peptide), this help is predominantly through CD4 T cell "licensing" of dendritic cells and other antigen presenting cells to express costimulatory molecules required to initiate T cell differentiation.…”

Section: Cd4 T Cells: the Cd8 T Rm And T Ex Helpersmentioning

confidence: 99%

“…Work by the Fabry group indicated that CXCL13 was expressed by inflamed endothelial cells in the brain following an infarct and served to recruit CXCR5 + IL21-producing CD4 T cells to sites of inflammation [108]. Although other mechanisms may be engaged to recruit T cells to the brain (e.g., CXCL9/10: CXCR3) [7,76,78], CXCL13:CXCR5 may act to aggregate CD4 and CD8 T cells in close proximity in nonlymphoid tissues and thereby facilitate CD4 T cell crosstalk with CD8 T cells. In this connection, CXCL13 + cells are present in the infected cerebral ventricular lining juxtaposed with aggregates of CD4 and CD8 T cells in the periventricular zone in brains of MuPyV-infected mice (HMR, unpublished observations).…”

Section: Significance Of Cxcr5mentioning

confidence: 99%

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IL-21 in Homeostasis of Resident Memory and Exhausted CD8 T Cells during Persistent Infection

Ren

Lukacher

2020

IJMS

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CD4 T cells guide the development of CD8 T cells into memory by elaborating mitogenic and differentiation factors and by licensing professional antigen-presenting cells. CD4 T cells also act to stave off CD8 T cell dysfunction during repetitive antigen stimulation in persistent infection and cancer by mitigating generation of exhausted T cells (TEX). CD4 T cell help is also required for establishing and maintaining tissue-resident memory T cells (TRM), the nonrecirculating memory T cell subset parked in nonlymphoid tissues to provide frontline defense against reinvading pathogens. Interleukin (IL)-21 is the signature cytokine secreted by follicular helper CD4 T cells (TFH) to drive B cell expansion and differentiation in germinal centers to mount high-affinity, isotype class-switched antibodies. In several infection models, IL-21 has been identified as the CD4 T help needed for formation and survival of TRM and TEX. In this review, we will explore the different memory subsets of CD8 T cells in persistent infections, the metabolic profiles associated with each, and evidence documenting the importance of CD4 T cell-derived IL-21 in regulating CD8 TRM and TEX development, homeostasis, and function.

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A quantitative LC–MS/MS method for the determination of tissue brincidofovir and cidofovir diphosphate in a MuPyV‐infected mouse model

Guzman

Schauer

Dunn

et al. 2021

Biomedical Chromatography

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Brincidofovir (BCV) is an investigational lipid conjugate of the nucleotide analog cidofovir (CDV), which is being developed as a medical countermeasure for the treatment of smallpox. BCV is active against double‐stranded DNA viruses including BK and JC viruses. Here, we validated procedures for quantifying BCV and its pharmacologically active moiety cidofovir diphosphate (CDV‐PP) in mouse kidney, brain and spleen tissue homogenates. Following homogenization, BCV and CDV‐PP were extracted from the tissues by protein precipitation with their stable, isotopically labeled internal standards, BCV‐d6 and 13C315N2‐CDV‐PP. Then, samples were analyzed for BCV by reverse‐phase chromatography on a Waters Xterra MS C18 (50 × 2.1 mm, 3.5 μm particle size) column while CDV‐PP was analyzed on a Thermo BioBasic AX (50 × 2.1 mm, 5 μm particle size) column using anion exchange chromatography. Detection was achieved by electrospray ionization in positive ion mode on an AB Sciex API‐5000 triple quadrupole mass spectrometer. The calibration curves were linear over a range of 1.00–1,000 ng/ml homogenate and 0.050–50.0 ng/ml homogenate for BCV and CDV‐PP, respectively. These methods were validated according to US Food and Drug Administration guidance for industry and may be used to characterize the tissue pharmacology of both analytes to advance its preclinical development.

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CD4 T cells control development and maintenance of brain-resident CD8 T cells during polyomavirus infection

Cited by 32 publications

References 96 publications

CD8 T Cells and STAT1 Signaling Are Essential Codeterminants in Protection from Polyomavirus Encephalopathy

CD8 T Cells and STAT1 Signaling Are Essential Codeterminants in Protection from Polyomavirus Encephalopathy

IL-21 in Homeostasis of Resident Memory and Exhausted CD8 T Cells during Persistent Infection

A quantitative LC–MS/MS method for the determination of tissue brincidofovir and cidofovir diphosphate in a MuPyV‐infected mouse model

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