The Opposing Effect of Type I IFN on the T Cell Response by Non-modified mRNA-Lipoplex Vaccines Is Determined by the Route of Administration

ABSTRACTMouse polyomavirus (MPyV) is a ubiquitous persistent natural mouse pathogen. A glutamic acid (E)-to-glycine (G) difference at position 91 of the VP1 capsid protein shifts the profile of tumors induced by MPyV from an epithelial to a mesenchymal cell origin. Here we asked if this tropism difference affects the MPyV-specific CD8 T cell response, which controls MPyV infection and tumorigenesis. Infection by the laboratory MPyV strain RA (VP1-91G) or a strain A2 mutant with an E-to-G substitution at VP1 residue 91 [A2(91G)] generated a markedly smaller virus-specific CD8 T cell response than that induced by A2(VP1-91E) infection. Mutant A2(91G)-infected mice showed a higher frequency of memory precursor (CD127hiKLRG1lo) CD8 T cells and a higher recall response than those of A2-infected mice. Using T cell receptor (TCR)-transgenic CD8 T cells and immunization with peptide-pulsed dendritic cells, we found that early bystander inflammation associated with A2 infection contributed to recruitment of the larger MPyV-specific CD8 T cell response. Beta interferon (IFN-β) transcripts were induced early during A2 or A2(91G) infections. IFN-β inhibited replication of A2 and A2(91G)in vitro. Using mice lacking IFN-αβ receptors (IFNAR−/−), we showed that type I IFNs played a role in controlling MPyV replicationin vivobut differentially affected the magnitude and functionality of virus-specific CD8 T cells recruited by A2 and A2(91G) viral infections. These data indicate that type I IFNs are involved in protection against MPyV infection and that their effect on the antiviral CD8 T cell response depends on capsid-mediated tropism properties of the MPyV strain.IMPORTANCEIsolates of the human polyomavirus JC virus from patients with the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML) carry single amino acid substitutions in the domain of the VP1 capsid protein that binds the sialic acid moiety of glycoprotein/glycolipid receptors on host cells. These VP1 mutations may alter neural cell tropism or enable escape from neutralizing antibodies. Changes in host cell tropism can affect recruitment of virus-specific CD8 T cells. Using mouse polyomavirus, we demonstrate that a single amino acid difference in VP1 known to shift viral tropism profoundly affects the quantity and quality of the anti-polyomavirus CD8 T cell response and its differentiation into memory cells. These findings raise the possibility that CD8 T cell responses to infections by human polyomaviruses may be influenced by VP1 mutations involving domains that engage host cell receptors.

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Blocking Virus Replication during Acute Murine Cytomegalovirus Infection Paradoxically Prolongs Antigen Presentation and Increases the CD8+T Cell Response by Preventing Type I IFN–Dependent Depletion of Dendritic Cells

The Journal of Immunology ◽

10.4049/jimmunol.1600478 ◽

2016 ◽

Vol 198 (1) ◽

pp. 383-393 ◽

Cited By ~ 5

Author(s):

Christopher P. Loo ◽

Christopher M. Snyder ◽

Ann B. Hill

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Antigen Presentation ◽

Virus Replication ◽

Cell Response ◽

Cytomegalovirus Infection ◽

Cd8 T Cell ◽

T Cell Response ◽

Murine Cytomegalovirus ◽

Type I

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A Fully Protective Congenital CMV Vaccine Requires Neutralizing Antibodies to Viral Pentamer and gB Glycoprotein Complexes but a pp65 T-Cell Response Is Not Necessary

Viruses ◽

10.3390/v13081467 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1467

Author(s):

K. Yeon Choi ◽

Alistair McGregor

Keyword(s):

T Cell ◽

Cell Response ◽

Neutralizing Antibodies ◽

T Cell Response ◽

Control Group ◽

Type I ◽

Cmv Infection ◽

Viral Glycoprotein ◽

Congenital Cmv Infection ◽

Congenital Cmv

A vaccine against congenital cytomegalovirus infection is a high priority. Guinea pig cytomegalovirus (GPCMV) is the only congenital CMV small animal model. GPCMV encodes essential glycoprotein complexes for virus entry (gB, gH/gL/gO, gM/gN) including a pentamer complex (gH/gL/GP129/GP131/GP133 or PC) for endocytic cell entry. The cohorts for protection against congenital CMV are poorly defined. Neutralizing antibodies to the viral glycoprotein complexes are potentially more important than an immunodominant T-cell response to the pp65 protein. In GPCMV, GP83 (pp65 homolog) is an evasion factor, and the GP83 mutant GPCMV has increased sensitivity to type I interferon. Although GP83 induces a cell-mediated response, a GP83-only-based vaccine strategy has limited efficacy. GPCMV attenuation via GP83 null deletion mutant in glycoprotein PC positive or negative virus was evaluated as live-attenuated vaccine strains (GP83dPC+/PC-). Vaccinated animals induced antibodies to viral glycoprotein complexes, and PC+ vaccinated animals had sterilizing immunity against wtGPCMV challenge. In a pre-conception vaccine (GP83dPC+) study, dams challenged mid-2nd trimester with wtGPCMV had complete protection against congenital CMV infection without detectable virus in pups. An unvaccinated control group had 80% pup transmission rate. Overall, gB and PC antibodies are key for protection against congenital CMV infection, but a response to pp65 is not strictly necessary.

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The NS2 Protein of Human Respiratory Syncytial Virus Suppresses the Cytotoxic T-Cell Response as a Consequence of Suppressing the Type I Interferon Response

Journal of Virology ◽

10.1128/jvi.01773-06 ◽

2006 ◽

Vol 80 (20) ◽

pp. 10286-10286

Author(s):

Alexander Kotelkin ◽

Igor M. Belyakov ◽

Lijuan Yang ◽

Jay A. Berzofsky ◽

Peter L. Collins ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

T Cell ◽

Cell Response ◽

Type I Interferon ◽

T Cell Response ◽

Human Respiratory Syncytial Virus ◽

Interferon Response ◽

Cytotoxic T Cell ◽

Type I ◽

Syncytial Virus

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miRNA-31 regulates the CD8 T cell response to type I IFNs during chronic infection

Cellular and Molecular Immunology ◽

10.1038/cmi.2017.80 ◽

2017 ◽

Vol 15 (4) ◽

pp. 402-404 ◽

Cited By ~ 1

Author(s):

Marta Catalfamo

Keyword(s):

T Cell ◽

Cell Response ◽

Chronic Infection ◽

Cd8 T Cell ◽

T Cell Response ◽

Type I ◽

Type I Ifns

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Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I–driven CD8+ T cell response

Journal of Experimental Medicine ◽

10.1084/jem.20172094 ◽

2018 ◽

Vol 215 (8) ◽

pp. 1987-1998 ◽

Cited By ~ 18

Author(s):

Krista Stockenhuber ◽

Ahmed N. Hegazy ◽

Nathaniel R. West ◽

Nicholas E. Ilott ◽

Alexander Stockenhuber ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Skin Inflammation ◽

Cd8 T Cell ◽

T Cell Response ◽

Mononuclear Phagocytes ◽

Psoriatic Skin ◽

Type I

Psoriasis is a complex inflammatory skin disease affecting ∼3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN-I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin. Mononuclear phagocytes (MNPs) were the source of IFN-I, and their depletion reversed the effect of T reg cell depletion. Blockade of IFN-I signaling abolished CD8+ T cell infiltration and excess inflammation in the skin of T reg cell–depleted mice. Depletion of CD8+ T cells attenuated pathology, confirming their role as critical effector cells downstream of IFN-I. Our results describe an unexpected role for T reg cells in restraint of an MNP–IFN-I–driven CD8+ T cell response during psoriasiform skin inflammation. These findings highlight a pathway with potential relevance for the treatment of early-stage disease.

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