scholarly journals Virus-Specific and Bystander CD8+T-Cell Proliferation in the Acute and Persistent Phases of a Gammaherpesvirus Infection

2001 ◽  
Vol 75 (9) ◽  
pp. 4435-4438 ◽  
Author(s):  
Gabrielle T. Belz ◽  
Peter C. Doherty
Keyword(s):  
T Cells ◽  
Cell Division ◽  
T Cell ◽  
Specific Response ◽  
Turnover Rates ◽  
Murine Gammaherpesvirus ◽  
Proliferation Of Lymphocytes ◽  
Antigenic Exposure ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT The cycling characteristics of CD8+ T cells specific for two lytic-phase epitopes of murine gammaherpesvirus 68 (γHV68) have been analyzed for mice with high or low levels of virus persistence. The extent of cell division is generally reflective of the antigen load and suggests that γHV68 may be regularly reactivating from latency for some months after the resolution of the acute phase of the infectious process. Although γHV68 infection is also associated with massive proliferation of lymphocytes that are not obviously specific for the virus, the level of “bystander-induced” cycling in a population of influenza virus-specific CD8+ T cells was generally fourfold lower than the extent of cell division seen for the antigen-driven, γHV68-specific response. The overall conclusion is that turnover rates substantially in excess of 5 to 10% over 6 days for CD8+ “memory” T-cell populations are likely to be reflective of continued antigenic exposure.

scholarly journals The CD8 T-Cell Response against Murine Gammaherpesvirus 68 Is Directed toward a Broad Repertoire of Epitopes from both Early and Late Antigens

2008 ◽  
Vol 82 (24) ◽  
pp. 12205-12212 ◽  
Author(s):  
Sara Gredmark-Russ ◽  
Evelyn J. Cheung ◽  
Marisa K. Isaacson ◽  
Hidde L. Ploegh ◽  
Gijsbert M. Grotenbreg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Ex Vivo ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Infection of mice with murine gammaherpesvirus 68 (MHV-68) robustly activates CD8 T cells, but only six class I major histocompatibility complex (MHC)-restricted epitopes have been described to date for the widely used H-2 b haplotype mice. To explore the specificity and kinetics of the cytotoxic T-lymphocyte response in MHV-68-infected C57BL/6 mice, we screened for H-2Kb- and H-2Db-restricted epitopes using a set of 384 candidate epitopes in an MHC tetramer-based approach and identified 19 new epitopes in 16 different open reading frames. Of the six known H-2Kb- and H-2Db-restricted epitopes, we confirmed a response against three and did not detect CD8 T-cell-specific responses for the remaining three. The peak of the CD8 T-cell response to most peptides occurs between 6 and 10 days postinfection. The respective MHC tetramer-positive CD8 T cells display an activated/effector phenotype (CD62Llo and CD44hi) and produce gamma interferon upon peptide stimulation ex vivo. MHV-68 infection in vivo elicits a response to multiple viral epitopes, derived from both early and late viral antigens, illustrating a far broader T-cell repertoire and more-rapid activation than those previously recorded.

scholarly journals CD80 and CD86 Control Antiviral CD8+ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

2006 ◽  
Vol 80 (18) ◽  
pp. 9159-9170 ◽  
Author(s):  
Shinichiro Fuse ◽  
Joshua J. Obar ◽  
Sarah Bellfy ◽  
Erica K. Leung ◽  
Weijun Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Immune Surveillance ◽  
Viral Reactivation ◽  
Classical Pathway ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT The interactions between CD80 and CD86 on antigen-presenting cells and CD28 on T cells serve as an important costimulatory signal in the activation of T cells. Although the simplistic two-signal hypothesis has been challenged in recent years by the identification of different costimulators, this classical pathway has been shown to significantly impact antiviral humoral and cellular immune responses. How the CD80/CD86-CD28 pathway affects the control of chronic or latent infections has been less well characterized. In this study, we investigated its role in antiviral immune responses against murine gammaherpesvirus 68 (MHV-68) and immune surveillance using CD80/CD86−/− mice. In the absence of CD80/CD86, primary antiviral CD8+ T-cell responses and the induction of neutralizing antibodies were severely impaired. During long-term immune surveillance, the virus-specific CD8+ T cells were impaired in IFN-γ production and secondary expansion and exhibited an altered phenotype. Surprisingly, a low level of viral reactivation in the lung was observed, and this effect was independent of CD28 and CTLA-4. Thus, CD80 and CD86, signaling through CD28 and possibly another unidentified receptor, are required for optimal immune surveillance and antiviral immune responses to murine gammaherpesvirus.

scholarly journals CD40 Engagement on Dendritic Cells, but Not on B or T Cells, Is Required for Long-Term Control of Murine Gammaherpesvirus 68

2008 ◽  
Vol 82 (22) ◽  
pp. 11016-11022 ◽  
Author(s):  
Francesca Giannoni ◽  
Ashley Shea ◽  
Chandra Inglis ◽  
Lian Ni Lee ◽  
Sally R. Sarawar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Viral Reactivation ◽  
Cd4 T Cell ◽  
Murine Gammaherpesvirus ◽  
Cd40 Expression ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT CD4 T cells are not essential for primary clearance of replicating murine gammaherpesvirus 68 (MHV-68) but are required for effective long-term control. The virus reactivates in the lungs of major histocompatibility complex class II-deficient (CII−/−) mice that lack functional CD4 T cells. CD40 ligand (CD40L) is upregulated on activated CD4 T cells, and it is thought that CD40-CD40L interactions are an important component of CD4 T-cell help. Our previous studies have shown that agonistic antibodies to CD40 can substitute for CD4 T-cell function in the long-term control of MHV-68. In the present study, we sought to identify the CD40-positive cell type mediating this effect. To address this question, we adoptively transferred MHV-68 peptide-pulsed CII−/− dendritic cells (DC) that had been treated with an agonistic antibody to CD40 into MHV-68-infected CII−/− recipients. Viral reactivation was significantly lower in mice injected with anti-CD40-treated DC than in those injected with control DC or in mice that did not receive any DC. However, in similar experiments with B cells, anti-CD40 treatment had no effect. We also investigated the requirement for CD40 expression on T cells by adoptive transfer of T cells from CD40+/+ or CD40−/− mice into T-cell-deficient recipients that were subsequently infected with MHV-68. The results showed that CD40 expression on T cells is not necessary for preventing viral reactivation. Taken together, our data suggest that CD40 engagement on DC, but not on T or B cells, is essential for effective long-term control of MHV-68.

scholarly journals Quantitative analysis of the CD8 + T–cell response to readily eliminated and persistent viruses

2000 ◽  
Vol 355 (1400) ◽  
pp. 1093-1101 ◽  
Author(s):  
P. C. Doherty ◽  
J. M. Riberdy ◽  
G. T. Belz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Flow Cytometric Analysis ◽  
T Cell Response ◽  
Basic Question ◽  
Cell Mediated Immunity ◽  
Specific Response ◽  
Turnover Rates

The recent development of techniques for the direct staining of peptide–specific CD8 + T cells has revolutionized the analysis of cell–mediated immunity (CMI) in virus infections. This approach has been used to quantify the acute and long–term consequences of infecting laboratory mice with the readily eliminated influenza A viruses (fluA) and a persistent γherpesvirus (γHV). It is now, for the first time, possible to work with real numbers in the analysis of CD8 + T CMI, and to define various characteristics of the responding lymphocytes both by direct flow cytometric analysis and by sorting for further in vitro manipulation. Relatively little has yet been done from the latter aspect, though we are rapidly accumulating a mass of numerical data. The acute, antigen–driven phases of the fluA and γHV–specific response look rather similar, but CD8 + T–cell numbers are maintained in the long term at a higher ‘set point’ in the persistent infection. Similarly, these ‘memory’ T cells continue to divide at a much greater rate in the γHV–infected mice. New insights have also been generated on the nature of the recall response following secondary challenge in both experimental systems, and the extent of protection conferred by large numbers of virus–specific CD8 + T cells has been determined. However, there are still many parameters that have received little attention, partly because they are difficult to measure. These include the rate of antigen–specific CD8 + T–cell loss, the extent of the lymphocyte ‘diaspora’ to other tissues, and the diversity of functional characteristics, turnover rates, clonal life spans and recirculation profiles. The basic question for immunologists remains how we reconcile the extraordinary plasticity of the immune system with the mechanisms that maintain a stable milieu interieur. This new capacity to quantify CD8 + T–cell responses in readily manipulated mouse models has obvious potential for illuminating homeostatic control, particularly if the experimental approaches to the problem are designed in the context of appropriate predictive models.

scholarly journals Two Kinetic Patterns of Epitope-Specific CD8 T-Cell Responses following Murine Gammaherpesvirus 68 Infection

2010 ◽  
Vol 84 (6) ◽  
pp. 2881-2892 ◽  
Author(s):  
Michael L. Freeman ◽  
Kathleen G. Lanzer ◽  
Tres Cookenham ◽  
Bjoern Peters ◽  
John Sidney ◽  
...  
Keyword(s):  
T Cell ◽  
Expression Patterns ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Immune Control ◽  
Murine Gammaherpesvirus ◽  
Cell Responses ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Murine gammaherpesvirus 68 (γHV68) provides an important experimental model for understanding mechanisms of immune control of the latent human gammaherpesviruses. Antiviral CD8 T cells play a key role throughout three separate phases of the infection: clearance of lytic virus, control of the latency amplification stage, and prevention of reactivation of latently infected cells. Previous analyses have shown that T-cell responses to two well-characterized epitopes derived from ORF6 and ORF61 progress with distinct kinetics. ORF6487-specific cells predominate early in infection and then decline rapidly, whereas ORF61524-specific cells continue to expand through early latency, due to sustained epitope expression. However, the paucity of identified epitopes to this virus has limited our understanding of the overall complexities of CD8 T-cell immune control throughout infection. Here we screened 1,383 predicted H-2b-restricted peptides and identified 33 responses, of which 21 have not previously been reported. Kinetic analysis revealed a spectrum of T-cell responses based on the rapidity of their decline after the peak acute response that generally corresponded to the expression patterns of the two previously characterized epitopes. The slowly declining responses that were maintained during latency amplification proliferated more rapidly and underwent maturation of functional avidity over time. Furthermore, the kinetics of decline was accelerated following infection with a latency-null mutant virus. Overall, the data show that γHV68 infection elicits a highly heterogeneous CD8 T-cell response that segregates into two distinctive kinetic patterns controlled by differential epitope expression during the lytic and latency amplification stages of infection.

scholarly journals Mononucleosis and Antigen-Driven T Cell Responses Have Different Requirements for Interleukin-2 Signaling in Murine Gammaherpesvirus Infection

2010 ◽  
Vol 84 (20) ◽  
pp. 10923-10927 ◽  
Author(s):  
Michael Molloy ◽  
Weijun Zhang ◽  
Edward Usherwood
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
T Cell Response ◽  
Long Term Memory ◽  
Murine Gammaherpesvirus ◽  
Cell Responses ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Interleukin-2 (IL-2) has been implicated as being necessary for the optimal formation of primary CD8+ T cell responses against various pathogens. Here we have examined the role that IL-2 signaling plays in several aspects of a CD8+ T cell response against murine gammaherpesvirus 68 (MHV-68). Exposure to MHV-68 causes a persistent infection, along with infectious mononucleosis, providing a model for studying these processes in mice. Our study indicates that CD25 is necessary for optimal expansion of the antigen-specific CD8+ T cell response but not for the long-term memory response. Contrastingly, IL-2 signaling through CD25 is absolutely required for CD8+ T cell mononucleosis.

scholarly journals CD4 T Cells Mediate Killing during Persistent Gammaherpesvirus 68 Infection

2009 ◽  
Vol 83 (9) ◽  
pp. 4700-4703 ◽  
Author(s):  
Kathleen A. Stuller ◽  
Emilio Flaño
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Persistently Infected ◽  
Murine Gammaherpesvirus ◽  
Cytotoxicity Assays ◽  
Gammaherpesvirus 68 ◽  
In Vivo Cytotoxicity ◽  
Murine Gammaherpesvirus 68

ABSTRACT CD4 T cells are critical for the control of gammaherpesvirus persistence, but their direct effector mechanisms of virus control in vivo are still poorly understood. In this study, we use murine gammaherpesvirus 68 (γHV68) in in vitro and in vivo cytotoxicity assays to show CD4-dependent killing of γHV68-loaded cells in mice persistently infected with γHV68. Our results underscore the cytotoxic capacity of CD4 T cells during γHV68 persistence.

Interactions of Murine Gammaherpesvirus 68 with B and T Cell Lines

Virology ◽  
1993 ◽  
Vol 193 (2) ◽  
pp. 825-833 ◽  
Author(s):  
N.P. Sunil-Chandra ◽  
S. Efstathiou ◽  
A.A. Nash
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68 ◽  
T Cell Lines ◽  
Murine Gammaherpesvirus 68

scholarly journals Infection of neonates with murine gammaherpesvirus 68 results in enhanced viral persistence in lungs and absence of infectious mononucleosis syndrome

2008 ◽  
Vol 89 (5) ◽  
pp. 1114-1121 ◽  
Author(s):  
Catherine Ptaschinski ◽  
Rosemary Rochford
Keyword(s):  
T Cell ◽  
Infectious Mononucleosis ◽  
Acute Infection ◽  
Viral Dna ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Age Dependent ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

We used the murine gammaherpesvirus 68 (γHV-68), which serves as a model for human gammaherpesvirus infection, to determine whether age at infection altered the pattern of gammaherpesvirus pathogenesis. We infected mice intranasally at 8 days old (pups) and 6 weeks old (adults) to investigate differences in γHV-68 pathogenesis. There was no difference between adults or pups in acute infection in the lungs at 6 days post-infection (p.i.). However, mice infected as pups exhibited a more disseminated viral infection with viral DNA detected in the spleen, liver and heart as measured by quantitative PCR (Q-PCR). In addition, viral DNA was detected in the lungs of mice infected as pups until 60 days p.i. Three viral transcripts (M2, M3 and M9) were expressed at both 30 and 60 days p.i. In contrast, no viral DNA or mRNA expression was detected in lungs of mice infected as adults at 30 or 60 days p.i. Mice infected as adults experienced a peak in latent infection in the spleen at 16 days p.i., corresponding with an increase in splenic weight and expansion of the Vβ4+ CD8+ T-cell population, similar to infectious mononucleosis observed following infection of young adults with Epstein–Barr virus. However, the increase in splenic weight of infected pups was not as pronounced and no significant increase in Vβ4+ CD8+ T-cell expansion was observed in infected pups. Together, these data suggest that the pathogenesis of murine gammaherpesvirus γHV-68 is age-dependent.

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