Early Virus-Associated Bystander Events Affect the Fitness of the CD8 T Cell Response to Persistent Virus Infection

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The CD8 coreceptor is important for positive selection of major histocompatibility complex I (MHC-I)-restricted thymocytes and in the generation of pathogen-specific T cells. However, the requirement for CD8 in these processes may not be essential. We previously showed that mice lacking ␤ 2 -microglobulin are highly susceptible to tumors induced by mouse polyoma virus (PyV), but CD8-deficient mice are resistant to these tumors. In this study, we show that CD8-deficient mice also control persistent PyV infection as efficiently as wild-type mice and generate a substantial virus-specific, MHC-I-restricted, T-cell response. Infection with vesicular stomatitis virus (VSV), which is acutely cleared, also recruited antigen-specific, MHC-I-restricted T cells in CD8-deficient mice. Yet, unlike in VSV infection, the antiviral MHC-I-restricted T-cell response to PyV has a prolonged expansion phase, indicating a requirement for persistent infection in driving T-cell inflation in CD8-deficient mice. Finally, we show that the PyV-specific, MHC-I-restricted T cells in CD8-deficient mice, while maintained long term at near-wild-type levels, are short lived in vivo and have extremely narrow T-cell receptor repertoires. These findings provide a possible explanation for the resistance of CD8-deficient mice to PyV-induced tumors and have implications for the maintenance of virus-specific MHC-I-restricted T cells during persistent infection.

Section: Methodsmentioning

confidence: 99%

Generation of Antiviral Major Histocompatibility Complex Class I-Restricted T Cells in the Absence of CD8 Coreceptors

Andrews

Pack

Lukacher

2008

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“…LP strains of MPyV disseminate more extensively than do SP strains (5,6). Administration of a low dose of the LP strain A2 delays the kinetics of expansion, but not the magnitude, of the MPyV-specific CD8 T cell response (23). We therefore asked whether B6 mice infected with an LP strain (A2) or an SP strain (RA) showed differences in viral dissemination and in the magnitude of the strongly dominant D b -restricted CD8 T cell response to amino acids 359 to 368 of the large T (LT) antigen, designated D b LT359 (48).…”

Section: Resultsmentioning

confidence: 99%

“…A2 and MPyV.LT206 have similar growth kinetics in vitro and in vivo (22). A recombinant vesicular stomatitis virus carrying the LT359 -368 sequence (rVSV-LT359) was generated as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

“…Memory CD8 T cells generated in response to infections that are cleared after acute infection selfrenew in an antigen-independent manner. We previously reported that CD8 T cells recruited early in a high-dose MPyV infection undergo exhaustion during the persistent phase of infection (22); however, the less inflammatory environment associated with early infection after low-dose MPyV inoculation favors differentiation of memory CD8 T cells with improved effector function (23). Different pathogen-induced inflammatory environments play an important role in controlling proliferation and effector and memory differentiation of CD8 T cells (17,24).…”

mentioning

confidence: 99%

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Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus-Specific CD8 T Cells in a Virus Strain-Dependent Manner

Qin

Shwetank

Frost

et al. 2016

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Mouse polyomavirus (MPyV) is a ubiquitous persistent natural mouse pathogen. A glutamic acid (E)-to-glycine (G) difference 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. Binding specificity among polyomaviruses is determined by interaction of the VP1 major capsid protein with host cell gangliosides having particular terminal sialic acid linkages (1). The gangliosides GD1a and GT1b are required for transport of mouse polyomavirus (MPyV) to the endoplasmic reticulum (2, 3). Discrete amino acid differences in the receptor binding site of VP1 impart important biological differences, including profound differences in pathogenicity (4). Replacement of the glycine (G) at position 91 of VP1 of the laboratory-derived small-plaque (SP) MPyV strain RA with glutamic acid (E), the amino acid at this position in the naturally occurring large-plaque (LP) strain PTA, was sufficient to convert it into a strain with an LP morphology and to alter the profile of induced tumors from a mesenchymal to an epithelial cell lineage (5). Alternatively, substitution of G for E at position 91 in VP1 in PTA had the opposite effect on plaque size and tumorigenicity (6, 7). In SP strains, VP1 capsids with G-91 interact with branched (␣-2,6)-linked sialyloligosaccharides, which may act as pseudoreceptors by binding cell surface glycoproteins that divert virions into noninfectious pathways (8). An E at this position in VP1 leads to electrostatic repulsion of the (␣-2,6)-linked sialic acids, thereby preventing binding of such branched structures by LP strains; however, binding to gangliosides with sialic acid (␣-2,3)-linked to galactose is retained for virion uptake into an infectious pathway (9, 10). Interestingly, MPyVs isolated from feral mice have exclusively E-91 VP1s, an unexpected finding given that such LP viruses are potentially more oncogenic than G-91 SP viruses (11).The human polyomavirus JC virus (JCV) is a frequent member of the human virome (12). Mutations of JCV capsid protein VP1

“…Our present finding that unhelped memory MT389-specific CD8 ϩ T cells (which do not express CD94/NKG2A) do not expand following Ag challenge provides additional support for the idea that CD94/NKG2A identifies a subpopulation of proliferation-competent antiviral memory CD8 ϩ T cells. We and others have shown that inflammation is detrimental to the differentiation of Ag-specific effector and memory CD8 ϩ T cells (1,3,4). Recently, Badovinac and Harty suggested that the degree of inflammation elicited by microbial infection is directly proportional to the duration and magnitude of the effector phase of the CD8 ϩ T-cell response (3).…”

Section: Discussionmentioning

confidence: 99%

Allogeneic Differences in the Dependence on CD4⁺T-Cell Help for Virus-Specific CD8⁺T-Cell Differentiation

Kemball

Szomolanyi-Tsuda

Lukacher

2007

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CD4؉ T-cell help enables antiviral CD8 ؉ T cells to differentiate into fully competent memory cells and sustains CD8؉ T-cell-mediated immunity during persistent virus infection. We recently reported that mice of C57BL/6 and C3H strains differ in their dependence on CD28 and CD40L costimulation for long-term control of infection by polyoma virus, a persistent mouse pathogen. In this study, we asked whether mice of these inbred strains also vary in their requirement for CD4 ؉ T-cell help for generating and maintaining polyoma virus-specific CD8 ؉ T cells. CD4 ؉ T-cell-depleted C57BL/6 mice mounted a robust antiviral CD8 ؉ T-cell response during acute infection, whereas unhelped CD8 ؉ T-cell effectors in C3H mice were functionally impaired during acute infection and failed to expand upon antigenic challenge during persistent infection. Using (C57BL/6 ؋ C3H)F 1 mice, we found that the dispensability for CD4 ؉ T-cell help for the H-2 b -restricted polyoma virus-specific CD8 ؉ T-cell response during acute infection extends to the H-2 k -restricted antiviral CD8 ؉ T cells. Our findings demonstrate that dependence on CD4 ؉ T-cell help for antiviral CD8 ؉ T-cell effector differentiation can vary among allogeneic strains of inbred mice.