scholarly journals CD28 Costimulation Is Required for Development of Herpetic Stromal Keratitis but Does Not Prevent Establishment of Latency

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Xiao-Tang Yin ◽  
Nicholas K. Baugnon ◽  
Chloe A. Potter ◽  
Shannon Tai ◽  
Tammie L. Keadle ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Wild Type ◽  
Corneal Disease ◽  
Herpetic Stromal Keratitis ◽  
Cd28 Costimulation ◽  
Stromal Keratitis ◽  
Simplex Virus

ABSTRACTCorneal infection with herpes simplex virus 1 (HSV-1) leads to infection of trigeminal ganglia (TG), typically followed by the establishment of latency in the infected neurons. When latency is disrupted, the virus reactivates and migrates back to the cornea, where it restimulates the immune response, leading to lesions in a disease called herpetic stromal keratitis (HSK). HSK requires T cell activation, as in the absence of T cells there is no disease. We decided to determine if CD28 costimulation of T cells was required in HSK. The results indicated that C57BL/6 CD28−/−and BALB/c CD28−/−mice failed to develop recurrent HSK, while their wild-type counterparts did. In order to better understand the dynamics of TG infection in these mice, we evaluated the amount of virus in infected TG and the number of individual neurons harboring latent virus. The results indicated that CD28−/−mice possessed significantly increased genome levels in their TG but many fewer LAT-positive cells than wild-type mice from day 7 to day 30 but that after day 30 these differences became nonsignificant. We next evaluated total and antigen-specific CD8+T cells in TG. The results indicated that there were significantly fewer CD8 T cells in TG from day 10 to day 25 but that after that the differences were not significant. Taken together, these data suggest that CD28 costimulation is required for HSK but that while initial infection of TG is greater in CD28−/−mice, this begins to normalize with time and this normalization is concurrent with the delayed development of antigen-specific CD8+T cells.IMPORTANCEWe study the pathogenesis of herpes simplex virus-mediated corneal disease. T cells play a critical role both in disease and in the maintenance of latency in neurons. Consequently, the focus of this study was to evaluate the role that T cell costimulation plays both in corneal disease and in controlling the ability of the virus to maintain a stable infection of the ganglia that innervate the cornea. We demonstrate that in the absence of costimulation with CD28, corneal disease does not take place. However, this costimulation does not prevent the ability of CD8+T cells to develop and, thus, control latent infection of neurons. We conclude from these studies that CD28 costimulation is required for corneal destructive immune responses but that CD8+T cells develop over time and help to maintain latency.

scholarly journals Dendritic Cell Autophagy Contributes to Herpes Simplex Virus-Driven Stromal Keratitis and Immunopathology

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Yike Jiang ◽  
Xiaotang Yin ◽  
Patrick M. Stuart ◽  
David A. Leib
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Herpetic Stromal Keratitis ◽  
Stromal Keratitis ◽  
Simplex Virus

ABSTRACTHerpetic stromal keratitis (HSK) is a blinding ocular disease that is initiated by HSV-1 and characterized by chronic inflammation in the cornea. Although HSK immunopathology of the cornea is well documented in animal models, events preceding this abnormal inflammatory cascade are poorly understood. In this study, we have examined the activation of pathological CD4+T cells in the development of HSK. Dendritic cell autophagy (DC-autophagy) is an important pathway regulating major histocompatibility complex class II (MHCII)-dependent antigen presentation and proper CD4+T cell activation during infectious diseases. Using DC-autophagy-deficient mice, we found that DC-autophagy significantly and specifically contributes to HSK disease without impacting early innate immune infiltration, viral clearance, or host survival. Instead, the observed phenotype was attributable to the abrogated activation of CD4+T cells and reduced inflammation in HSK lesions. We conclude that DC-autophagy is an important contributor to primary HSK immunopathology upstream of CD4+T cell activation.IMPORTANCEHerpetic stromal keratitis (HSK) is the leading cause of infectious blindness in the United States and a rising cause worldwide. HSK is induced by herpes simplex virus 1 but is considered a disease of inappropriately sustained inflammation driven by CD4+T cells. In this study, we investigated whether pathways preceding CD4+T cell activation affect disease outcome. We found that autophagy in dendritic cells significantly contributed to the incidence of HSK. Dendritic cell autophagy did not alter immune control of the virus or neurological disease but specifically augmented CD4+T cell activation and pathological corneal inflammation. This study broadens our understanding of the immunopathology that drives HSK and implicates the autophagy pathway as a new target for therapeutic intervention against this incurable form of infectious blindness.

scholarly journals Identification and Characterization of Herpes Simplex Virus‐Specific CD4+T Cells in Corneas of Herpetic Stromal Keratitis Patients

1998 ◽  
Vol 177 (2) ◽  
pp. 484-488 ◽  
Author(s):  
Georges M. G. M. Verjans ◽  
Lies Remeijer ◽  
Robert S. van Binnendijk ◽  
José G. C. Cornelissen ◽  
Hennie J. Völker‐Dieben ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cd4 T Cells ◽  
Herpetic Stromal Keratitis ◽  
Stromal Keratitis ◽  
Simplex Virus ◽  
Identification And Characterization

scholarly journals CD8+ T cells control corneal disease following ocular infection with herpes simplex virus type 1

2004 ◽  
Vol 85 (7) ◽  
pp. 2055-2063 ◽  
Author(s):  
Patrick M. Stuart ◽  
Brett Summers ◽  
Jessica E. Morris ◽  
Lynda A. Morrison ◽  
David A. Leib
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Herpes Simplex Virus Type ◽  
T Cell Subsets ◽  
Trigeminal Ganglia ◽  
Corneal Disease ◽  
Simplex Virus

The role that T cell subsets play in herpetic stromal keratitis (HSK) has been the subject of intense research efforts. While most studies implicate CD4+ T cells as the principal cell type mediating primary corneal disease, recent reports using knockout mice have suggested that both CD4+ and CD8+ T cell subsets may play integral roles in modulating the disease. Furthermore, recent studies suggest that CD8+ T cells are directly involved in maintaining virus latency in infected trigeminal ganglia. This work has addressed these discrepancies by infecting the corneas of mice lacking CD4+ and CD8+ T cells with herpes simplex virus type 1 (HSV-1) and monitoring both corneal disease and latent infection of trigeminal ganglia. Results indicated that mice lacking CD8+ T cells had more severe corneal disease than either BALB/c or B6 parental strains. In contrast, mice lacking CD4+ T cells had a milder disease than parental strains. When mice were evaluated for persistence of infectious virus, only transient differences were observed in periocular tissue and corneas. No significant differences were found in persistence of virus in trigeminal ganglia or virus reactivation from explanted ganglia. These data support the following conclusions. CD4+ T cells are not required for resistance to infection with HSV-1 and probably mediate HSK. Mice lacking CD8+ T cells do not display differences in viral loads or reactivation and thus CD8+ T cells are not absolutely required to maintain latency. Finally, CD8+ T cells probably play a protective role by regulating the immunopathological response that mediates HSK.

Characterization of herpes simplex virus (HSV) specific T cells isolated from corneas of patients with herpetic stromal keratitis

1997 ◽  
Vol 56 ◽  
pp. 22-23
Author(s):  
G.M.G.M. Verjans ◽  
L. Remeijer ◽  
R.S. van Binnendijk ◽  
J. Cornelissen ◽  
H.J. Völker-Dieben ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpetic Stromal Keratitis ◽  
Stromal Keratitis ◽  
Simplex Virus

scholarly journals Herpes Simplex Virus 1 (HSV-1) 0ΔNLS Live-Attenuated Vaccine Protects against Ocular HSV-1 Infection in the Absence of Neutralizing Antibody in HSV-1 gB T Cell Receptor-Specific Transgenic Mice

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Grzegorz B. Gmyrek ◽  
Adrian Filiberti ◽  
Micaela Montgomery ◽  
Alisha Chitrakar ◽  
Derek J. Royer ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Neutralizing Antibody ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Attenuated Virus ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The contribution of T cell and antibody responses following vaccination in resistance to herpes simplex virus 1 (HSV-1) infection continues to be rigorously investigated. In the present article, we explore the contribution of CD8+ T cells specific for the major antigenic epitope for HSV-1 glycoprotein B (gB498–505, gB) in C57BL/6 mice using a transgenic mouse (gBT-I.1) model vaccinated with HSV-1 0ΔNLS. gBT-I.1-vaccinated mice did not generate a robust neutralization antibody titer in comparison to the HSV-1 0ΔNLS-vaccinated wild-type C57BL/6 counterpart. Nevertheless, the vaccinated gBT-I.1 mice were resistant to ocular challenge with HSV-1 compared to vehicle-vaccinated animals based on survival and reduced corneal neovascularization but displayed similar levels of corneal opacity. Whereas there was no difference in the virus titer recovered from the cornea comparing vaccinated mice, HSV-1 0ΔNLS-vaccinated animals possessed significantly less infectious virus during acute infection in the trigeminal ganglia (TG) and brain stem compared to the control-vaccinated group. These results correlated with a significant increase in gB-elicited interferon-γ (IFN-γ), granzyme B, and CD107a and a reduction in lymphocyte activation gene 3 (LAG-3), programmed cell death 1 (PD-1), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) expressed by TG infiltrating gB-specific CD8+ T cells from the HSV-1 0ΔNLS-vaccinated group. Antibody depletion of CD8+ T cells in HSV-1 0ΔNLS-vaccinated mice rendered animals highly susceptible to virus-mediated mortality similar to control-vaccinated mice. Collectively, the HSV-1 0ΔNLS vaccine is effective against ocular HSV-1 challenge, reducing ocular neovascularization and suppressing peripheral nerve virus replication in the near absence of neutralizing antibody in this unique mouse model. IMPORTANCE The role of CD8+ T cells in antiviral efficacy using a live-attenuated virus as the vaccine is complicated by the humoral immune response. In the case of the herpes simplex virus 1 (HSV-1) 0ΔNLS vaccine, the correlate of protection has been defined to be primarily antibody driven. The current study shows that in the near absence of anti-HSV-1 antibody, vaccinated mice are protected from subsequent challenge with wild-type HSV-1 as measured by survival. The efficacy is lost following depletion of CD8+ T cells. Whereas increased survival and reduction in virus replication were observed in vaccinated mice challenged with HSV-1, cornea pathology was mixed with a reduction in neovascularization but no change in opacity. Collectively, the study suggests CD8+ T cells significantly contribute to the host adaptive immune response to HSV-1 challenge following vaccination with an attenuated virus, but multiple factors are involved in cornea pathology in response to ocular virus challenge.

scholarly journals Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10

2007 ◽  
Vol 81 (22) ◽  
pp. 12504-12514 ◽  
Author(s):  
Derek D. Sloan ◽  
Keith R. Jerome
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
T Cell Receptor ◽  
Intracellular Signaling ◽  
Cell Function ◽  
Cell Receptor ◽  
Interleukin 10 ◽  
Simplex Virus

ABSTRACT Herpes simplex virus (HSV)-specific T cells are essential for viral clearance. However, T cells do not prevent HSV latent infection or reactivation, suggesting that HSV has the potential to modulate T-cell function. T-cell receptor (TCR) stimulation is a potent and specific means of activating T cells. To investigate how HSV affects T-cell function, we have analyzed how HSV affects TCR-stimulated intracellular signaling and cytokine synthesis in mock-infected and HSV-infected T cells. Mock-infected T cells stimulated through the TCR synthesized a broad range of cytokines that included the proinflammatory cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-2. In contrast, HSV-infected T cells stimulated through the TCR selectively synthesized interleukin-10, a cytokine that suppresses cellular immunity and favors viral replication. To achieve selective interleukin-10 synthesis, HSV differentially affected TCR signaling pathways. HSV inhibited TCR-stimulated formation of the linker for activation of the T-cell signaling complex, and HSV inhibited TCR-stimulated NF-κB activation. At the same time, HSV activated the p38 and JNK mitogen-activated protein kinases as well as the downstream transcription factors ATF-2 and c-Jun. HSV did not inhibit TCR-stimulated activation of STAT3, a transcription factor involved in interleukin-10 synthesis. The activation of p38 was required for interleukin-10 synthesis in HSV-infected T cells. The ability of HSV to differentially target intracellular signaling pathways and transform an activating stimulus into an immunosuppressive response represents a novel strategy for pathogen-mediated immune modulation. Selective, TCR-stimulated interleukin-10 synthesis may play an important role in HSV pathogenesis.

scholarly journals Protective T-Cell-Based Immunity Induced in Neonatal Mice by a Single Replicative Cycle of Herpes Simplex Virus

2001 ◽  
Vol 75 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Marco Franchini ◽  
Carlos Abril ◽  
Cornelia Schwerdel ◽  
Christiane Ruedl ◽  
Mathias Ackermann ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Newborn Mice ◽  
Virus Challenge ◽  
Virus Particles ◽  
Simplex Virus ◽  
Replicative Cycle ◽  
Hsv 1

ABSTRACT Newborns are very susceptible to infections because their immune systems are not fully developed and react to antigen exposure preferentially with unresponsiveness. UV-inactivated herpes simplex virus type 1 (HSV-1) represents such an antigen and does not induce an immune response in neonates. In contrast, protective T cells were primed in newborn mice by a single replicative cycle of DISC HSV-1 given once within 24 h of birth. Each of the HSV-1-primed CD4+ or CD8+ T cells induced in wild-type or interferon-deficient mice conferred resistance to naive animals exposed to a lethal virus challenge. Inactivated HSV-1, injected at variable doses up to 104 times that of DISC HSV-1, was ineffective in inducing any detectable immune responses in neonates. Thus, the capacity of HSV-1 to replicate once, but not the number of virus particles per se, was decisive in inducing protective T-cell-associated immunity in newborn mice.

Sign in / Sign up

Export Citation Format

Share Document