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

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.

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

Viruses ◽

10.3390/v13030359 ◽

2021 ◽

Vol 13 (3) ◽

pp. 359

Author(s):

Thomas R. O’Neil ◽

Kevin Hu ◽

Naomi R. Truong ◽

Sana Arshad ◽

Barbara L. 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 recently been increased interest in defining the phenotype and the role of CD4+ TRM in diseases. Circulating CD4+ T cells seed 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 the 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.

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HLA-E Up-Regulation Induced by HIV Infection May Directly Contribute to CD94-Mediated Impairment of NK Cells

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463200501800209 ◽

2005 ◽

Vol 18 (2) ◽

pp. 269-276 ◽

Cited By ~ 26

Author(s):

F. Martini ◽

C. Agrati ◽

G. D'Offizi ◽

F. Poccia

Keyword(s):

T Cells ◽

Hiv Infection ◽

Nk Cells ◽

Cd4 T Cells ◽

Nk Cell ◽

Treatment Interruption ◽

Cell Number ◽

Hiv Replication

Alterations in NK cell numbers and function have been repeatedly shown during HIV infection. In this study, NK cell number and MHC class I expression on CD4+ T cells were studied in HIV patients at different stages of disease progression. An increased expression of HLA-E was seen on CD4+ T cells. In parallel, a reduced number of CD94+ NK cells was observed in advanced disease stages. Moreover, a decline in CD94 expression on NK cells was observed at the HIV replication peak in patients undergoing antiretroviral treatment interruption, suggesting a role of viral replication on NK cells alterations. In vitro HIV infection induced a rapid down-regulation of HLA-A,B,C expression, paralleled by an increased expression of HLA-E surface molecules, the formal ligands of CD94 NK receptors. HIV-infected HLA-E expressing cells were able to inhibit NK cell cytotoxicity through HLA-E expression, since cytotoxicity was restored by antibody masking experiments. These data indicate that the CD94/HLA-E interaction may contribute to NK cell dysfunction in HIV infection, suggesting a role of HIV replication in this process.

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The Role of Pre-existing Cross-Reactive Central Memory CD4 T-Cells in Vaccination With Previously Unseen Influenza Strains

Frontiers in Immunology ◽

10.3389/fimmu.2019.00593 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 4

Author(s):

Mikalai Nienen ◽

Ulrik Stervbo ◽

Felix Mölder ◽

Sviatlana Kaliszczyk ◽

Leon Kuchenbecker ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Central Memory ◽

Memory Cd4 T Cells

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HIV replication in conjunction with granzyme B production by CCR5+ memory CD4 T cells: Implications for bystander cell and tissue pathologies

Virology ◽

10.1016/j.virol.2014.06.008 ◽

2014 ◽

Vol 462-463 ◽

pp. 175-188 ◽

Cited By ~ 8

Author(s):

Jacob Couturier ◽

Alexander T. Hutchison ◽

Miguel A. Medina ◽

Cosmina Gingaras ◽

Petri Urvil ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Granzyme B ◽

Bystander Cell ◽

Hiv Replication ◽

Memory Cd4 T Cells

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

Science ◽

10.1126/science.1257530 ◽

2014 ◽

Vol 346 (6205) ◽

pp. 93-98 ◽

Cited By ~ 217

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.

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Blind Uneven Proliferation of CD4+ T cells During Primary Infection Generates the Majority of the HIV Reservoir

10.1101/2020.04.06.20053231 ◽

2020 ◽

Author(s):

Florencia A. T. Boshier ◽

Daniel B. Reeves ◽

Elizabeth R. Duke ◽

David A. Swan ◽

Martin Prlic ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Cellular Proliferation ◽

Chromosomal Dna ◽

Hiv Replication ◽

Hiv Reservoir ◽

Viral Spread ◽

Hiv Dna ◽

Latently Infected ◽

Memory Cd4 T Cells

AbstractThe HIV reservoir is a population of 1-10 million anatomically dispersed, latently infected memory CD4+ T cells in which an HIV DNA molecule is quiescently integrated into human chromosomal DNA. When antiretroviral therapy (ART) is stopped and HIV replication initiates in one of these cells, systemic viral spread resumes, rekindling progression to AIDS. Therefore, HIV latency prevents cure. The HIV reservoir contains clones: identical HIV sequences that are integrated within identical human chromosomal DNA locations. The presence of these clones demonstrates that proliferation of CD4+ T cells sustains infection despite ART. The reservoir has a precise structure consisting of a small number of large clones and a large number of small clones. However, the mechanisms leading to this structure have not been identified. We developed a mathematical model that recapitulates the profound depletion and brisk recovery of CD4+ T cells, reservoir creation, and viral load trajectory during primary HIV infection. We extended the model to simulate stochastically individual HIV reservoir clones and identified that uneven proliferation among clones during recovery from CD4+ lymphopaenia is sufficient to explain the observed clonal reservoir distribution. We project that within one month of infection 75-95% of reservoir cells are generated from cellular proliferation rather than denovo viral infection. Recent detection of HIV infected clones during the first 5 weeks of infection support our model’s predictions.

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Dysfunctional Senescent Herpes Simplex Virus Specific CD57+CD8+ T cells are Associated with Recurrent Symptomatic Herpes in Humans

10.1101/2022.01.05.475169 ◽

2022 ◽

Author(s):

Lbachir BenMohamed ◽

Arif A. Khan ◽

Ruchi Srivastava ◽

Hawa Vahed

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Cd8 T Cells ◽

High Frequency ◽

Recurrent Herpes ◽

Natural Protection ◽

Simplex Virus ◽

And Function

Herpes simplex virus (HSV)-specific CD8+ T cells protect mice from herpes infection and disease. However, the phenotype and function of HSV-specific CD8+ T cells that play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. We previously reported that symptomatic (SYMP) patients (who have frequent bouts of recurrent herpes disease) had more less-differentiated and dysfunctional HSV-specific CD8+ T cells. In contrast, healthy ASYMP individuals maintained a significantly higher proportion of differentiated polyfunctional CD8+ T cells. Here we report that, HSV-specific CD8+ T cells from SYMP patients, but not from ASYMP individuals, have phenotypic and functional characteristics of cellular senescence, including: (i) high frequency of senescent (CD57+) and exhausted (PD-1+) CD8+ T cells; (ii) late terminally differentiated (KLRG1+), non-proliferating CD8+ T cells; (iii) HSV-specific CD8+ T cells were declined overtime and were not maintained homeostatistically (CD127+CD8+ T cells); (iv) loss of co-stimulatory molecule (CD28)on HSV-specific CD8+ T cells; (v) decreased production of effector molecules (granzyme B and perforin) by HSV-specific CD8+ T cells. Our findings provide insights into the role of senescence in HSV-specific CD8+ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.

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Role of Regulated Upon Activation Normal T-Cell Expressed and Secreted in a Model of Retransplantation Acute Rejection Mediated by Alloreactive Memory CD4+ T Cells

Transplantation Proceedings ◽

10.1016/j.transproceed.2012.11.005 ◽

2013 ◽

Vol 45 (2) ◽

pp. 546-551 ◽

Cited By ~ 3

Author(s):

X. Zhou ◽

Z. Shan ◽

H. Liang ◽

Z. Lin ◽

S. Qiu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Acute Rejection ◽

Cd4 T Cells ◽

Memory Cd4 T Cells

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CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses

Journal of Experimental Medicine ◽

10.1084/jem.20181365 ◽

2019 ◽

Vol 216 (5) ◽

pp. 1214-1229 ◽

Cited By ~ 46

Author(s):

Lalit K. Beura ◽

Nancy J. Fares-Frederickson ◽

Elizabeth M. Steinert ◽

Milcah C. Scott ◽

Emily A. Thompson ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Activation ◽

Immune Cell ◽

Memory T Cells ◽

Cell Immunity ◽

And Migration ◽

Resident Memory T Cells ◽

Memory Cd4 T Cells

This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property–specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4+ TRM reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4+ T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8+ T cells.

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