Blocking 4-1BB/4-1BB Ligand Interactions Prevents Herpetic Stromal Keratitis

Seo, Su K.; Park, Hye Y.; Choi, Jae Hoon; Kim, Won Yong; Kim, Young H.; Jung, Hyo Won; Kwon, Byungsuk; Lee, Hyeon W.; Kwon, Byoung S.

doi:10.4049/jimmunol.171.2.576

Cited by 54 publications

(47 citation statements)

References 29 publications

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“…In in vivo viral infection models, 4-1BB costimulation has been shown to affect mainly the antiviral CD8 ϩ T cell response (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Interestingly, studies by Bertram et al (22,23) have revealed a specific role for 4-1BB costimulation in the maintenance of memory CD8…”

Section: Ostimulatory Signals Provide Secondary Signals To T Cells mentioning

confidence: 99%

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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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Section: Ostimulatory Signals Provide Secondary Signals To T Cells mentioning

confidence: 99%

“…The kinetics of 4-1BB expression during infection with HSV is also transient, although the peak of expression differs with the route of infection (27,29). We sought to analyze the expression of 4-1BB on virusspecific CD8…”

Section: T Cells During Mhv-68 Infection 4-1bb Expression On Cd8mentioning

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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“…In graft-vs-host disease models, 4-1BB/4-1BBL can play an equivalent role in MHC-I-or MHC-II-restricted disease (28), although the same is not true for OX40 (29). Furthermore, 4-1BB is required for herpes simplex 1-mediated keratinitis (30), a disease that has been attributed to the Th1 response. In adoptive transfer models, using OVA-specific TCR transgenic T cells, both OX40 and 4-1BB costimulatory pathways can influence CD4 and CD8 responses (6,(31)(32)(33).…”

mentioning

confidence: 99%

4-1BB and OX40 Act Independently to Facilitate Robust CD8 and CD4 Recall Responses

Dawicki

Bertram

Sharpe

et al. 2004

The Journal of Immunology

136

111

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Mice deficient in OX40 or 4-1BB costimulatory pathways show defects in T cell recall responses, with predominant effects on CD4 vs CD8 T cells, respectively. However, OX40L can also stimulate CD8 T cells and 4-1BBL can influence CD4 T cells, raising the possibility of redundancy between the two TNFR family costimulators. To test this possibility, we generated mice deficient in both 4-1BBL and OX40L. In an adoptive transfer model, CD4 T cells expressed 4-1BB and OX40 sequentially in response to immunization, with little or no overlap in the timing of their expression. Under the same conditions, CD8 T cells expressed 4-1BB, but no detectable OX40. Thus, in vivo expression of 4-1BB and OX40 can be temporally and spatially segregated. In the absence of OX40L, there were decreased CD4 T cells late in the primary response and no detectable secondary expansion of adoptively transferred CD4 T cells under conditions in which primary expansion was unaffected. The 4-1BBL had a minor effect on the primary response of CD4 T cells in this model, but showed larger effects on the secondary response, although 4-1BBL−/− mice show less impairment in CD4 secondary responses than OX40L−/− mice. The 4-1BBL−/− and double knockout mice were similarly impaired in the CD8 T cell response, whereas OX40L−/− and double knockout mice were similarly impaired in the CD4 T cell response to both protein Ag and influenza virus. Thus, 4-1BB and OX40 act independently and nonredundantly to facilitate robust CD4 and CD8 recall responses.

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“…However, bystander activation of CD4 + T cells in addition to virus antigen stimulation may also contribute to HSK development [24]. The continued expression of chemokines including CXCL2, CCL2, CCL3, CCL4, CCL5, and CXCL10 in the cornea would also provide the maintenance of leukocytes in the tissue recruited from the periphery and facilitate collateral damage to the cornea stroma [84]. Collectively, chemokines are instrumental in the initial trafficking of cells into the infected anterior segment of the eye as well as the development of HSK.…”

Section: Adaptive Immune Response To Ocular Hsv-1 Infectionmentioning

confidence: 99%

Herpes Simplex Virus and the Chemokines That Mediate the Inflammation

Carr

Tomanek

Current Topics in Microbiology and Immunology

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Herpes simplex viruses (HSV) are highly pervasive pathogens in the human host with a seroconversion rate upwards of 60% worldwide. HSV type 1 (HSV-1) is associated with the disease, herpetic stromal keratitis, the leading cause of infectious corneal blindness in the industrialized world. Individuals suffering from genital herpes associated with HSV type 2 (HSV-2) are found to be two to three fold more susceptible in acquiring human immunodeficiency virus (HIV). The morbidity associated with these infections is principally due to the inflammatory response, the development of lesions, and scarring. Chemokines have become an important aspect in understanding the host immune response to microbial pathogens due in part to the timing of expression. In this paper, we will explore the current understanding of chemokine production as it relates to the orchestration of the immune response to HSV infection.

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Blocking 4-1BB/4-1BB Ligand Interactions Prevents Herpetic Stromal Keratitis

Cited by 54 publications

References 29 publications

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

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

4-1BB and OX40 Act Independently to Facilitate Robust CD8 and CD4 Recall Responses

Herpes Simplex Virus and the Chemokines That Mediate the Inflammation

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