Differential requirement for CD28 and CD80/86 pathways of costimulation in the long-term control of murine gammaherpesvirus-68

Lyon, Ashley; Sarawar, Sally R.

doi:10.1016/j.virol.2006.06.039

Cited by 17 publications

(31 citation statements)

References 35 publications

(50 reference statements)

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“…Consequently, these results indicate that the absence of B7.1/B7.2 has a more profound impact on the LCMV-specific immune response than does the lack of CD28, and the results may therefore suggest that there are additional stimulatory receptors for B7.1/B7.2 besides CD28. A few other studies have pointed toward the same conclusion (19)(20)(21), but so far no such receptor has been unequivocally identified.…”

Section: Discussionmentioning

confidence: 86%

“…In view of the fact that these issues had not been optimally dealt with in earlier studies on LCMV infection, we considered it important to revisit the role of CD28-B7 in inducing and maintaining LCMV-specific CD8 T cell memory, with the reason being that it would be very important to know if certain viruses would have the capacity to induce not only initial T cell activation, but also completely normal memory differentiation in the absence of this key costimulatory interaction. Our interest was further fueled by a few recent reports suggesting that there might be other stimulatory receptors for B7 than CD28 (19)(20)(21) and that earlier studies of the LCMV infection might have failed in finding a key role for B7 costimulation, because these studies had been performed in CD28 mice have no obvious phenotype following infection with MHV68, T cell-dependent immune surveillance eventually completely collapses in MHC class II-deficient mice, and, interestingly, analysis of B7.1/B7.2 2/2 mice revealed that these mice lay between these two extremes. This is similar to the situation in mice infected with moderate doses of rapidly invasive strains of LCMV, where the infection is efficiently controlled in CD28-deficient mice (17) but leads to late recrudescence of viremia and severe disease in MHC class II-deficient mice (22).…”

mentioning

confidence: 99%

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The Role of CD80/CD86 in Generation and Maintenance of Functional Virus-Specific CD8+ T Cells in Mice Infected with Lymphocytic Choriomeningitis Virus

Grujić

Bartholdy

Remy

et al. 2010

The Journal of Immunology

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Lymphocytic choriomeningitis virus (LCMV)-specific CD8(+) T cell responses are considered to be independent of CD28-B7 costimulation. However, the LCMV-specific response has never been evaluated in B7.1/B7.2(-/-) mice. For this reason, we decided to study the T cell response in B7.1/B7.2(-/-) mice infected with two different strains of LCMV, one (Traub strain) typically causing low-grade chronic infection, and another (Armstrong clone 53b) displaying very limited capacity for establishing chronic infection. Using Traub virus we found that most B7.1/B7.2(-/-) mice were unable to rid themselves of the infection. Chronic infection was associated with a perturbed CD8(+) T cell epitope hierarchy, as well as with the accumulation of cells expressing markers of terminal differentiation and being unable to respond optimally to Ag restimulation. Examination of matched CD28(-/-) mice revealed a similar albeit less pronounced pattern of CD8(+) T cell dysfunction despite lack of virus persistence. Finally, analysis of B7.1/B7.2(-/-) mice infected with Armstrong virus revealed a scenario quite similar to that in Traub infected CD28(-/-) mice; that is, the mice displayed evidence of T cell dysfunction, but no chronic infection. Taken together, these results indicate that B7 costimulation is required for induction and maintenance of LCMV-specific CD8(+) T cell memory, irrespective of the LCMV strain used for priming. However, the erosion of CD8(+) T cell memory in B7.1/B7.2(-/-) mice was more pronounced in association with chronic infection. Finally, virus-specific T cell memory was more impaired in the absence of B7 molecules than in the absence of the CD28 receptor, supporting earlier data suggesting the existence of additional stimulatory receptors for B7

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

The Role of CD80/CD86 in Generation and Maintenance of Functional Virus-Specific CD8+ T Cells in Mice Infected with Lymphocytic Choriomeningitis Virus

Grujić

Bartholdy

Remy

et al. 2010

The Journal of Immunology

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“…The CD40L-CD40 pathway is essential for long-term immunological control of latent infection (44,45). The CD80/CD86-CD28 pathway has a significant impact in the antiviral humoral (42,46), and cellular (46,47) responses, and low levels of viral reactivation during latency is observed in the lungs of CD80/CD86 Ϫ/Ϫ mice (47,48). In this study, we investigated the role of the 4-1BBL-4-1BB pathway in immune surveillance of MHV-68 infection.…”

Section: Ostimulatory Signals Provide Secondary Signals To T Cells mentioning

confidence: 99%

CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand

Fuse

Bellfy

Yagita

et al. 2007

The Journal of Immunology

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Studies of costimulatory receptors belonging to the TNFR family have revealed their diverse roles in affecting different stages of the T cell response. The 4-1BB ligand (4-1BBL)/4-1BB pathway has emerged as a receptor-ligand pair that impacts not the initial priming, but later phases of the T cell response, such as sustaining clonal expansion and survival, maintaining memory CD8+ T cells, and supporting secondary expansion upon Ag challenge. Although the role of this costimulatory pathway in CD8+ T cell responses to acute viral infections has been well-studied, its role in controlling chronic viral infections in vivo is not known to date. Using the murine gammaherpesvirus-68 (MHV-68) model, we show that 4-1BBL-deficient mice lack control of MHV-68 during latency and show significantly increased latent viral loads. In contrast to acute influenza infection, the numbers of MHV-68-specific memory CD8+ T cells were maintained during latency. However, the virus-specific CD8+ T cells showed defects in function, including decreased cytolytic function and impaired secondary expansion. Thus, 4-1BBL deficiency significantly affects the function, but not the number, of virus-specific CD8+ T cells during gammaherpesvirus latency, and its absence results in an increased viral burden. Our study suggests that the 4-1BB costimulatory pathway plays an important role in controlling chronic viral infections.

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“…For example, paralysis following local HSV-1 infection was aggravated by CTLA-4Ig-mediated CD80/86 blockade but not in CD28 Ϫ/Ϫ mice (20). Similarly, viral reactivation occurred in the lungs of MHV-68-infected CD80/86 Ϫ/Ϫ but not CD28 Ϫ/Ϫ (22,42,54), anti-CTLA-4-treated CD28 Ϫ/Ϫ (22), or CD28 Ϫ/Ϫ /CTLA-4 Ϫ/Ϫ mice (18), leading to the postulate of an unidentified (activating) receptor for CD80/86, a notion that has also been advanced in models of cardiac allograft transplantation (55,82). Most recently, primary MCMV-specific CD8 ϩ T E responses were shown to be somewhat more compromised in CD80/86 Ϫ/Ϫ or anti-CD80/86 antibody-treated wt mice than in CD28 Ϫ/Ϫ mice (3), and exacerbated phenotypic alterations and functional defects of CD8 ϩ T M populations combined with impaired virus control in CD80/86 Ϫ/Ϫ but not CD28 Ϫ/Ϫ mice infected with the more virulent LCMV Traub strain have prompted similar speculations about additional CD80/86 receptors (28).…”

mentioning

confidence: 98%

“…To date, infections with multiple distinct and related viruses, escalating dosages, and various challenge routes have been employed to ascertain the role of CD28-CD80/86 costimulation preferentially in CD28 Ϫ/Ϫ mice but also complemented by analyses of CD80 Ϫ/Ϫ and/or CD86 Ϫ/Ϫ strains as well as ligand (anti-CD80/86 and CTLA-4Ig) and receptor (anti-CD28 and anti-CTLA-4) blockade. These viruses include LCMV (1,15,25,28,36,44,45,65,69,72,73,81); vesicular stomatitis virus (VSV) (1, 15, 43-45, 58, 69); vaccinia virus (VACV) (21,23,24,45,67,70) and the related ectromelia virus (ECTV) (21); influenza A virus (5,7,8,10,14,29,32,51,53,74), herpes simplex viruses (herpes simplex virus 1 [HSV-1] and HSV-2) (10,20,75,76); murine gammaherpesvirus 68 (MHV-68) (18,22,24,42,47,54); polyomavirus (PyV) (41), murine cytomegalovirus (MCMV) (2,3,17); and adenovirus …”

mentioning

confidence: 99%

Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

Eberlein

Davenport

Nguyen

et al. 2012

J Virol

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The lymphocytic choriomeningitis virus (LCMV) system constitutes one of the most widely used models for the study of infectious disease and the regulation of virus-specific T cell immunity. However, with respect to the activity of costimulatory and associated regulatory pathways, LCMV-specific T cell responses have long been regarded as relatively independent and thus distinct from the regulation of T cell immunity directed against many other viral pathogens. Here, we have reevaluated the contribution of CD28-CD80/86 costimulation in the LCMV system by use of CD80/86-deficient mice, and our results demonstrate that a disruption of CD28-CD80/86 signaling compromises the magnitude, phenotype, and/or functionality of LCMVspecific CD8 ؉ and/or CD4 ؉ T cell populations in all stages of the T cell response. Notably, a profound inhibition of secondary T cell immunity in LCMV-immune CD80/86-deficient mice emerged as a composite of both defective memory T cell development and a specific requirement for CD80 but not CD86 in the recall response, while a related experimental scenario of CD28-dependent yet CD80/86-independent secondary CD8 ؉ T cell immunity suggests the existence of a CD28 ligand other than CD80/ 86. Furthermore, we provide evidence that regulatory T cells (T REG s), the homeostasis of which is altered in CD80/86 ؊/؊ mice, contribute to restrained LCMV-specific CD8 ؉ T cell responses in the presence of CD80/86. Our observations can therefore provide a more coherent perspective on CD28-CD80/86 costimulation in antiviral T cell immunity that positions the LCMV system within a shared context of multiple defects that virus-specific T cells acquire in the absence of CD28-CD80/86 costimulation.T he generation of specific T cell immunity is governed by multiple determinants that shape the proliferative expansion and functional maturation of effector T cells (T E ) as well as their subsequent differentiation into memory T cells (T M ). Conceptualization of these processes permits the straightforward demarcation of T cell receptor (TCR)-peptide/major histocompatibility complex (MHC) interactions ("signal 1"), yet the simple notion of a defined "costimulus" required for the optimization of specific T cell responses, historically referred to as "signal 2," has been eroded by the realization that a multiplicity of diverse receptor-ligand interactions between T cells and antigen-presenting cells (APCs), soluble factors (e.g., cytokines), and specific temporospatial constraints operate in concert to control the eventual magnitude as well as the molecular, phenotypic, and functional properties of responding T E populations. Thus, it is the integration of signals derived from a large complex of stimulatory and inhibitory interactions that permits activated T cells the translation of minimal kinetic alterations into profound modifications of the ensuing T cell response (26,84). Insofar as these interactions produce a kinetic, quantitative, and/or qualitative enhancement of specific T cell immunity, individual components with...

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Differential requirement for CD28 and CD80/86 pathways of costimulation in the long-term control of murine gammaherpesvirus-68

Cited by 17 publications

References 35 publications

The Role of CD80/CD86 in Generation and Maintenance of Functional Virus-Specific CD8+ T Cells in Mice Infected with Lymphocytic Choriomeningitis Virus

The Role of CD80/CD86 in Generation and Maintenance of Functional Virus-Specific CD8+ T Cells in Mice Infected with Lymphocytic Choriomeningitis Virus

CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand

Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

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