Selective Expression of CCR10 and CXCR3 by Circulating Human Herpes Simplex Virus-Specific CD8 T Cells

ABSTRACT Herpes simplex virus (HSV) infection is restricted to epithelial cells and neurons and is controlled by CD8 T cells. These cells both traffic to epithelial sites of recurrent lytic infection and to ganglia and persist at the dermal-epidermal junction for up to 12 weeks after lesion resolution. We previously showed that cutaneous lymphocyte-associated antigen (CLA), a functional E-selectin ligand (ESL), is selectively expressed on circulating HSV-2-specific CD8 T cells. CLA/ESL mediates adhesion of T cells to inflamed vascular endothelium. Later stages in T-cell homing involve chemokines (Ch) and lymphocyte chemokine receptors (ChR) for vascular wall arrest and diapedesis. Several candidate ChR have been implicated in skin homing. We measured cell surface ChR on HSV-specific human peripheral blood CD8 T cells and extended our studies to HSV-1. We observed preferential cell surface expression of CCR10 and CXCR3 by HSV-specific CD8 T cells compared to CD8 T cells specific for control viruses, Epstein-Barr virus (EBV) and cytomegalovirus (CMV), and compared to bulk memory CD8 T cells. CXCR3 ligand mRNA levels were selectively increased in skin biopsy specimens from persons with recurrent HSV-2, while the mRNA levels of the CCR10 ligand CCL27 were equivalent in lesion and control skin. Our data are consistent with a model in which CCL27 drives baseline recruitment of HSV-specific CD8 T cells expressing CCR10, while interferon-responsive CXCR3 ligands recruit additional cells in response to virus-driven inflammation. IMPORTANCE HSV-2 causes very localized recurrent infections in the skin and genital mucosa. Virus-specific CD8 T cells home to the site of recurrent infection and participate in viral clearance. The exit of T cells from the blood involves the use of chemokine receptors on the T-cell surface and chemokines that are present in infected tissue. In this study, circulating HSV-2-specific CD8 T cells were identified using specific fluorescent tetramer reagents, and their expression of several candidate skin-homing-associated chemokine receptors was measured using flow cytometry. We found that two chemokine receptors, CXCR3 and CCR10, are upregulated on HSV-specific CD8 T cells in blood. The chemokines corresponding to these receptors are also expressed in infected tissues. Vaccine strategies to prime CD8 T cells to home to HSV lesions should elicit these chemokine receptors if possible to increase the homing of vaccine-primed cells to sites of infection.

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CD8+ T Cells in the Central Nervous System of Mice With Herpes Simplex Infection are Highly Activated and Express High Levels of CCR5 and CXCR3

10.21203/rs.3.rs-39368/v1 ◽

2020 ◽

Author(s):

Liza Lind ◽

Alexandra Svensson ◽

Karolina Thörn ◽

Malgorzata Krzyzowska ◽

Kristina Eriksson

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

T Cells ◽

Nervous System ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Cd8 T Cells ◽

Chemokine Receptors ◽

The Central Nervous System ◽

Simplex Virus

Abstract Background: Herpes simplex virus type 2 (HSV-2) is a neurotropic virus that can cause meningitis, an inflammation of the meninges in the central nervous system. T cells are key players in viral clearance, and these cells migrate from peripheral blood into the central nervous system upon infection. Several factors contribute to T cell migration, including the expression of chemokines in the inflamed tissue that attract T cells through their expression of chemokine receptors. Here we investigated CD8+ T cell profile in the spinal cord in a mouse model of herpes simplex virus type 2neuroinflammation. Method: Mice were infected with HSV-2, and sacrificed when showing signs of neuroinflammation. Cells and/or tissue from spinal cord, spleen and bloodwere analyzed for viability, expression of activation markers, chemokinereceptors and chemokines. Statistics were calculated using students T test and one-way ANOVA.Results:High numbers of CD8+ T cellswere present in thespinal cord following genital HSV-2-infection.CD8+T cells were highly activated and HSV-2 glycoprotein B -specific effector cells, some of which showed signs of recent degranulation. They also expressed high levels of many chemokine receptors, in particular CCR2, CCR4, CCR5 and CXCR3. Investigating corresponding receptor ligands in spinal cord tissue revealed markedly increased expression of the cognate ligands CCL2, CCL5, CCL8,CCL12 and CXCL10. Conclusion: This study shows thatduring herpesvirus neuroinflammation anti-viralCD8+T cells accumulatein the CNS. CD8+ T cells in the CNS also express chemotactic receptors cognate to the chemotactic gradients in the spinal cord. This indicates that anti-viral CD8+ T cells may migrate to infected areas in the spinal cord during herpesvirus neuroinflammation in response to chemotactic gradients.

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Us3 Kinase Encoded by Herpes Simplex Virus 1 Mediates Downregulation of Cell Surface Major Histocompatibility Complex Class I and Evasion of CD8+ T Cells

PLoS ONE ◽

10.1371/journal.pone.0072050 ◽

2013 ◽

Vol 8 (8) ◽

pp. e72050 ◽

Cited By ~ 28

Author(s):

Takahiko Imai ◽

Naoto Koyanagi ◽

Ryo Ogawa ◽

Keiko Shindo ◽

Tadahiro Suenaga ◽

...

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Cell Surface ◽

Cd8 T Cells ◽

Complex Class ◽

Herpes Simplex Virus 1 ◽

Histocompatibility Complex ◽

Simplex Virus

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

Journal of Virology ◽

10.1128/jvi.01111-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12504-12514 ◽

Cited By ~ 39

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.

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Cd8+ T Cells Can Block Herpes Simplex Virus Type 1 (HSV-1) Reactivation from Latency in Sensory Neurons

Journal of Experimental Medicine ◽

10.1084/jem.191.9.1459 ◽

2000 ◽

Vol 191 (9) ◽

pp. 1459-1466 ◽

Cited By ~ 264

Author(s):

Ting Liu ◽

Kamal M. Khanna ◽

XiaoPing Chen ◽

David J. Fink ◽

Robert L. Hendricks

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Sensory Neurons ◽

Cd8 T Cells ◽

Early Proteins ◽

Latently Infected ◽

Simplex Virus ◽

Hsv 1

Recurrent herpes simplex virus type 1 (HSV-1) disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. Therefore, defining the mechanisms that maintain HSV-1 in a latent state in sensory neurons may provide new approaches to reducing susceptibility to recurrent herpetic disease. After primary HSV-1 corneal infection, CD8+ T cells infiltrate the trigeminal ganglia (TGs) of mice, and are retained in latently infected ganglia. Here we demonstrate that CD8+ T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures. Latently infected neurons expressed viral genome and some expressed HSV-1 immediate early and early proteins, but did not produce HSV-1 late proteins or infectious virions. Addition of anti-CD8α monoclonal antibody 5 d after culture initiation induced HSV-1 reactivation, as demonstrated by production of viral late proteins and infectious virions. Thus, CD8+ T cells can prevent HSV-1 reactivation without destroying the infected neurons. We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8+ T cells aborting virion production.

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Innate Immune Responses to Herpes Simplex Virus Type 2 Influence Skin Homing Molecule Expression by Memory CD4+ Lymphocytes

Journal of Virology ◽

10.1128/jvi.80.6.2863-2872.2006 ◽

2006 ◽

Vol 80 (6) ◽

pp. 2863-2872 ◽

Cited By ~ 12

Author(s):

David M. Koelle ◽

Jay Huang ◽

Michael T. Hensel ◽

Christopher L. McClurkan

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Cd4 T Cells ◽

Receptor Expression ◽

Homing Receptor ◽

Skin Homing ◽

Simplex Virus

ABSTRACT Herpes simplex virus (HSV) infections of humans are characterized by intermittent, lytic replication in epithelia. Circulating HSV-specific CD4 T cells express lower levels of preformed cutaneous lymphocyte-associated antigen (CLA), a skin-homing receptor, than do circulating HSV-specific CD8 T cells but, paradoxically, move into infected skin earlier than CD8 cells. Memory CD4 T cells develop strong and selective expression of CLA and E-selectin ligand while responding to HSV antigen in vitro. We now show that interleukin-12, type I interferon, and transforming growth factor beta are each involved in CLA expression by memory HSV type 2 (HSV-2)-specific CD4 T cells in peripheral blood mononuclear cells (PBMC). A reduction of the number of monocytes and dendritic cells from PBMC reduces CLA expression by HSV-2-responsive CD4 lymphoblasts, while their reintroduction restores this phenotype, identifying these cells as possible sources of CLA-promoting cytokines. Plasmacytoid dendritic cells are particularly potent inducers of CLA on HSV-reactive CD4 T cells. These observations are consistent with cooperation between innate and acquired immunity to promote a pattern of homing receptor expression that is physiologically appropriate for trafficking to infected tissues.

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

Journal of Virology ◽

10.1128/jvi.75.1.83-89.2001 ◽

2001 ◽

Vol 75 (1) ◽

pp. 83-89 ◽

Cited By ~ 43

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.

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Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons.

Journal of Experimental Medicine ◽

10.1084/jem.175.5.1337 ◽

1992 ◽

Vol 175 (5) ◽

pp. 1337-1344 ◽

Cited By ~ 179

Author(s):

A Simmons ◽

D C Tscharke

Keyword(s):

T Cells ◽

Nervous System ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Cd8 T Cells ◽

Genetic Determinants ◽

Histocompatibility Complex ◽

Sensory Nervous System ◽

Simplex Virus

The role of CD8+ T cells in resistance to herpes simplex virus (HSV) was examined. After cutaneous inoculation, HSV spreads to the peripheral nervous system (PNS) where it replicates in ganglionic neurons. In normal mice, replication of virus in the PNS was rapidly terminated and evidence of neuronal destruction, assessed by a quantitative histological assay, was sparse. Clearance of infectious virus was impaired, and a strikingly high proportion of ganglionic neurons was killed, in mice treated with an antibody that depleted them of CD8+ T cells. These results suggest that CD8+ T cells play an important role in maintaining the integrity of the sensory nervous system during primary infection with HSV. Therefore, viral epitopes recognized by CD8+ T cells and restricting class I major histocompatibility complex genes are, in principle, implicated as interacting genetic determinants of neurovirulence.

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Engagement of TLR2 Reverses the Suppressor Function of Conjunctiva CD4+CD25+Regulatory T Cells and Promotes Herpes Simplex Virus Epitope-Specific CD4+CD25−Effector T Cell Responses

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.10-6522 ◽

2011 ◽

Vol 52 (6) ◽

pp. 3321 ◽

Cited By ~ 13

Author(s):

Gargi Dasgupta ◽

Aziz Alami Chentoufi ◽

Sylvaine You ◽

Payam Falatoonzadeh ◽

Lourie Ann A. Urbano ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Responses ◽

Effector T Cell ◽

Cell Responses ◽

Virus Epitope ◽

Simplex Virus

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

Journal of General Virology ◽

10.1099/vir.0.80049-0 ◽

2004 ◽

Vol 85 (7) ◽

pp. 2055-2063 ◽

Cited By ~ 30

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.

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