scholarly journals A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells

Science ◽  
2014 ◽  
Vol 346 (6205) ◽  
pp. 93-98 ◽  
Author(s):  
Norifumi Iijima ◽  
Akiko Iwasaki
Keyword(s):  
T Cells ◽  
Herpes Simplex ◽  
Memory T Cells ◽  
Local Network ◽  
Sexually Transmitted ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Memory Cd4 T Cells ◽  
Full Protection

CD8 tissue-resident memory T (TRM) cells provide efficient local control of viral infection, but the role of CD4 TRM is less clear. Here, by using parabiotic mice, we show that a preexisting pool of CD4 TRM cells in the genital mucosa was required for full protection from a lethal herpes simplex virus 2 (HSV-2) infection. Chemokines secreted by a local network of macrophages maintained vaginal CD4 TRM in memory lymphocyte clusters (MLCs), independently of circulating memory T cells. CD4 TRM cells within the MLCs were enriched in clones that expanded in response to HSV-2. Our results highlight the need for vaccine strategies that enable establishment of TRM cells for protection from a sexually transmitted virus and provide insights as to how such a pool might be established.

scholarly journals Increased Frequency of Virus Shedding by Herpes Simplex Virus 2-Infected Guinea Pigs in the Absence of CD4+ T Lymphocytes

2018 ◽  
Vol 93 (4) ◽  
Author(s):  
Nigel Bourne ◽  
Clarice L. Perry ◽  
Brianne N. Banasik ◽  
Aaron L. Miller ◽  
Mellodee White ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Guinea Pigs ◽  
Cell Populations ◽  
Therapeutic Vaccines ◽  
Virus Shedding ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

ABSTRACT Reactivation of herpes simplex virus 2 (HSV-2) results in infection of epithelial cells at the neuro-epithelial junction and shedding of virus at the epithelial surface. Virus shedding can occur in either the presence or absence of clinical disease and is usually of short duration, although the shedding frequency varies among individuals. The basis for host control of virus shedding is not well understood, although adaptive immune mechanisms are thought to play a central role. To determine the importance of CD4+ T cells in control of HSV-2 shedding, this subset of immune cells was depleted from HSV-2-infected guinea pigs by injection of an anti-CD4 monoclonal antibody (MAb). Guinea pigs were treated with the depleting MAb after establishment of a latent infection, and vaginal swabs were taken daily to monitor shedding by quantitative PCR. The cumulative number of HSV-2 shedding days and the mean number of days virus was shed were significantly increased in CD4-depleted compared to control-treated animals. However, there was no difference in the incidence of recurrent disease between the two treatment groups. Serum antibody levels and the number of HSV-specific antibody-secreting cells in secondary lymphoid tissues were unaffected by depletion of CD4+ T cells; however, the frequency of functional HSV-specific, CD8+ gamma interferon-secreting cells was significantly decreased. Together, these results demonstrate an important role for CD4+ T lymphocytes in control of virus shedding that may be mediated in part by maintenance of HSV-specific CD8+ T cell populations. These results have important implications for development of therapeutic vaccines designed to control HSV-2 shedding. IMPORTANCE Sexual transmission of HSV-2 results from viral shedding following reactivation from latency. The immune cell populations and mechanisms that control HSV-2 shedding are not well understood. This study examined the role of CD4+ T cells in control of virus shedding using a guinea pig model of genital HSV-2 infection that recapitulates the shedding of virus experienced by humans. We found that the frequency of virus-shedding episodes, but not the incidence of clinical disease, was increased by depletion of CD4+ T cells. The HSV-specific antibody response was not diminished, but frequency of functional HSV-reactive CD8+ T cells was significantly diminished by CD4 depletion. These results confirm the role of cell-mediated immunity and highlight the importance of CD4+ T cells in controlling HSV shedding, suggesting that therapeutic vaccines designed to reduce transmission by controlling HSV shedding should include specific enhancement of HSV-specific CD4+ T cell responses.

scholarly journals Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Ming Lo ◽  
Jia Zhu ◽  
Scott G. Hansen ◽  
Timothy Carroll ◽  
Christina Farr Zuend ◽  
...  
Keyword(s):  
Animal Model ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epithelial Cells ◽  
Rhesus Macaques ◽  
Sexually Transmitted ◽  
Key Features ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Incident Cases

ABSTRACTHerpes simplex virus 2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study host–HSV-2 interactions, an animal model of subclinical HSV-2 infection is needed. In an effort to develop a relevant model, rhesus macaques (RM) were inoculated intravaginally with two or three HSV-2 strains (186, 333, and/or G) at a total dose of 1 × 107PFU of HSV-2 per animal. Infectious HSV-2 and HSV-2 DNA were consistently shed in vaginal swabs for the first 7 to 14 days after each inoculation. Proteins associated with wound healing, innate immunity, and inflammation were significantly increased in cervical secretions immediately after HSV-2 inoculation. There was histologic evidence of acute herpesvirus pathology, including acantholysis in the squamous epithelium and ballooning degeneration of and intranuclear inclusion bodies in epithelial cells, with HSV antigen in mucosal epithelial cells and keratinocytes. Further, an intense inflammatory infiltrate was found in the cervix and vulva. Evidence of latent infection and reactivation was demonstrated by the detection of spontaneous HSV-2 shedding post-acute inoculation (102to 103DNA copies/swab) in 80% of RM. Further, HSV-2 DNA was detected in ganglia in most necropsied animals. HSV-2-specifc T-cell responses were detected in all animals, although antibodies to HSV-2 were detected in only 30% of the animals. Thus, HSV-2 infection of RM recapitulates many of the key features of subclinical HSV-2 infection in women but seems to be more limited, as virus shedding was undetectable more than 40 days after the last virus inoculation.IMPORTANCEHerpes simplex virus 2 (HSV-2) infects nearly 500 million persons globally, with an estimated 21 million incident cases each year, making it one of the most common sexually transmitted infections (STIs). HSV-2 is associated with increased human immunodeficiency virus type 1 (HIV-1) acquisition, and this risk does not decline with the use of antiherpes drugs. As initial acquisition of both HIV and HSV-2 infections is subclinical, study of the initial molecular interactions of the two agents requires an animal model. We found that HSV-2 can infect RM after vaginal inoculation, establish latency in the nervous system, and spontaneously reactivate; these features mimic some of the key features of HSV-2 infection in women. RM may provide an animal model to develop strategies to prevent HSV-2 acquisition and reactivation.

Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus

2009 ◽  
Vol 10 (5) ◽  
pp. 524-530 ◽  
Author(s):  
Thomas Gebhardt ◽  
Linda M Wakim ◽  
Liv Eidsmo ◽  
Patrick C Reading ◽  
William R Heath ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Memory T Cells ◽  
Local Immunity ◽  
Simplex Virus ◽  
Nonlymphoid Tissue

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

1992 ◽  
Vol 175 (5) ◽  
pp. 1337-1344 ◽  
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.

Role of Lyt-1 Positive Immune T Cells in Recovery from Herpes Simplex Virus Infection in Mice

1982 ◽  
Vol 26 (4) ◽  
pp. 359-362 ◽  
Author(s):  
Seiho Nagafuchi ◽  
Isao Hayashida ◽  
Kazuo Higa ◽  
Toshio Wada ◽  
Ryoichi Mori
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Infection ◽  
Herpes Simplex Virus Infection ◽  
Simplex Virus

scholarly journals The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection

2020 ◽  
Author(s):  
Thomas Ray O'Neil ◽  
Kevin Hu ◽  
Naomi Truong ◽  
Sana Arshad ◽  
Barbara Shacklett ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex ◽  
Cd4 T Cells ◽  
Sexual Transmission ◽  
Trigeminal Ganglia ◽  
Hiv Replication ◽  
Recurrent Herpes ◽  
Resident Memory T Cells ◽  
Memory Cd4 T Cells

Tissue resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8 TRM, there has been recently an increased interest in defining the phenotype and the role of CD4 TRM in diseases. Circulating CD4 T cells seed tissue CD4 TRM, but there also appears to be an equilibrium between CD4 TRM and blood CD4 T cells. CD4 TRM are more mobile than CD8 TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8 TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4 and CD8 TRM persisting between lesions may control asymptomatic shedding through interferon gamma secretion, although this has been more clearly shown for CD8 T cells. The exact role of the CD4/CD8 TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4 TRM have now been shown to be a major target for productive and latent infection in cervix. In HSV and HIV co-infections, CD4 TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4 TRM and their induction by vaccines may help control sexual transmission by both viruses.

scholarly journals Correlation between detergent activity and anti-herpes simplex virus-2 activity of commercially available vaginal gels

2020 ◽  
Author(s):  
Andrea Szöllősi ◽  
Tímea Raffai ◽  
Anita Bogdanov ◽  
Valéria Endrész ◽  
László Párducz ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Hela Cells ◽  
Negative Impact ◽  
Inhibitory Effect ◽  
Sexually Transmitted ◽  
Viral Genomes ◽  
Vaginal Gels ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

Abstract Objective Herpes simplex virus-2 (HSV-2) infections are almost exclusively sexually transmitted. The presence of vaginal gels during the sexual activity may have a significant positive or negative impact on the viral transmission. Therefore we investigated three off-the-shelf vaginal lubricants and one pH restoring gel to evaluate their impact on HSV-2 replication. Results HeLa cells were infected with untreated virions and virions incubated with the particular gels. The accumulation of viral genomes was monitored by quantitative PCR (qPCR) method at 24 hours post infection. Two of the tested gels had no significant effect on HSV-2 replication at the maximum applied concentration, while two had a strong inhibitory effect (~ 98% reduction of replication). The replication inhibitory effect was observed at various multiplicity of infection (MOI 0.4-6.4) and the two inhibitory gels were also capable of inhibiting the HSV-2 induced cytopathic effect on HeLa cells. The surface tension decreasing activity - a sign of detergent activity - was strongly correlated with the anti-HSV-2 activity of the gels (R 2 : 0.88). Our results indicate that off-the-shelf vaginal gels have a markedly different anti-HSV-2 activity that may influence HSV-2 transmission.

scholarly journals Anti-Inflammatory Mechanism of Astragaloside IV in the Recurrence of Asthma: Critical Role of Memory T Cells and OX40/OX40L Signaling Pathway

2021 ◽  
Author(s):  
Qingqing Yang ◽  
Hongying Zhang ◽  
Jing Sun ◽  
Jingcheng Dong ◽  
Lingwen Kong
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Memory T Cells ◽  
Effector T Cells ◽  
Central Memory ◽  
Response Level ◽  
Inflammatory Mechanism ◽  
Before And After ◽  
Memory Cd4 T Cells

Abstract The recurrence of asthma is partly mediated by central memory CD4(+) T cells(TCM) that promote lung inflammation through the production of effector T cells. Targeting the expansion of pathogenic TCM(central memory CD4(+) T cells) is a promising therapeutic strategy to block production of effector T cells. The study aimed to evaluate the regulatory effects of Astragaloside IV (AS-IV) on TCMs and try to explore the anti-inflammatory mechanism of AS-IV in asthmatic mice. We developed a murine model of asthma by ovalbumin(OVA) challenge. Flow cytometry was used to determine the counts of CD4(+) memory T cells subgroups. Pulmonary tests, inflammatory cytokines in blood and inflammatory cells in bronchoalveolar lavage fluid,were measured to evaluate the inflammatory response level before and after AS-IV treatment. To further determine the role of TCM in the recurrence of inflammation, TCM were isolated by Magnetic-activated cell sorting (MACS) from spleens of asthma, control, AS-IV and dexamethasone treatment mice. The isolated cells were adoptive transferred into nude mice via tail intravenous injection, respectively, and the inflammatory response level of the lung was measured after OVA challenge. The effects of AS-IV on TCM viability, the number of the frequency (in percent) of CD44highCD62Lhigh cells, and the expression of OX40 and OX40L were measured before and after AS-IV treatment. In circulation blood, we demonstrated increased percentages of CCR7highCD62LlowCD4+ effector memory T cells(TEM) and decreased CCR7highCD62LhighCD4(+) TCM in asthma mice. On the contrary, the TEM subgroup percentage were decreased and the TCM phenotypes were increased in asthmatic spleen. AS-IV treatment significantly decreased CD4(+) T effector phenotypes in blood and inhibited the lung inflammatory response. Additionally, the inflammation of nude mice that adoptive transferred TCM from AS-IV treatment asthmatic mice had relieved inflammation compared with asthmatic group. In vitro, we successfully used spleen T lymphoid cells stimulated with IL-7 and OVA to induce a central memory T cell model. TCM co-cultured with DC cells had a significantly increased expression of OX40/OX40L. AS-IV pretreatment partially inhibited the expression of OX40 signal pathway. This study indicates that AS-IV can ameliorate asthma inflammation by inhibiting the production of TEM form TCM. The treatment mechanism maybe involved in the OX40/OX40L pathway.

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