Human Effector Memory CD4+ T Cells Directly Recognize Allogeneic Endothelial Cells In Vitro and In Vivo

ABSTRACT Simian immunodeficiency virus SIVrcm, which naturally infects red-capped mangabeys (RCMs), is the only SIV that uses CCR2 as its main coreceptor due to the high frequency of a CCR5 deletion in RCMs. We investigated the dynamics of SIVrcm infection to identify specific pathogenic mechanisms associated with this major difference in SIV biology. Four pigtailed macaques (PTMs) were infected with SIVrcm, and infection was monitored for over 2 years. The dynamics of in vivo SIVrcm replication in PTMs was similar to that of other pathogenic and nonpathogenic lymphotropic SIVs. Plasma viral loads (VLs) peaked at 107 to 109 SIVrcm RNA copies/ml by day 10 postinoculation (p.i.). A viral set point was established by day 42 p.i. at 103 to 105 SIVrcm RNA copies/ml and lasted up to day 180 p.i., when plasma VLs decreased below the threshold of detection, with blips of viral replication during the follow-up. Intestinal SIVrcm replication paralleled that of plasma VLs. Up to 80% of the CD4+ T cells were depleted by day 28 p.i. in the gut. The most significant depletion (>90%) involved memory CD4+ T cells. Partial CD4+ T-cell restoration was observed in the intestine at later time points. Effector memory CD4+ T cells were the least restored. SIVrcm strains isolated from acutely infected PTMs used CCR2 coreceptor, as reported, but expansion of coreceptor usage to CCR4 was also observed. Selective depletion of effector memory CD4+ T cells is in contrast with predicted in vitro tropism of SIVrcm for macrophages and is probably due to expansion of coreceptor usage. Taken together, these findings emphasize the importance of understanding the selective forces driving viral adaptation to a new host.

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The Interplay of HIV-1 and Macrophages in Viral Persistence

Frontiers in Microbiology ◽

10.3389/fmicb.2021.646447 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chynna M. Hendricks ◽

Thaissa Cordeiro ◽

Ana Paula Gomes ◽

Mario Stevenson

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Viral Persistence ◽

Vital Role ◽

Highly Active ◽

Antiretroviral Therapies ◽

Memory Cd4 T Cells ◽

Hiv 1

HIV-1 has evolved mechanisms to evade host cell immune responses and persist for lifelong infection. Latent cellular reservoirs are responsible for this persistence of HIV-1 despite the powerful effects of highly active antiretroviral therapies (HAART) to control circulating viral load. While cellular reservoirs have been extensively studied, much of these studies have focused on peripheral blood and resting memory CD4+ T cells containing latent HIV-1 provirus; however, efforts to eradicate cellular reservoirs have been stunted by reservoirs found in tissues compartments that are not easily accessible. These tissues contain resting memory CD4+ T cells and tissue resident macrophages, another latent cellular reservoir to HIV-1. Tissue resident macrophages have been associated with HIV-1 infection since the 1980s, and evidence has continued to grow regarding their role in HIV-1 persistence. Specific biological characteristics play a vital role as to why macrophages are latent cellular reservoirs for HIV-1, and in vitro and in vivo studies exhibit how macrophages contribute to viral persistence in individuals and animals on antiretroviral therapies. In this review, we characterize the role and evolutionary advantages of macrophage reservoirs to HIV-1 and their contribution to HIV-1 persistence. In acknowledging the interplay of HIV-1 and macrophages in the host, we identify reasons why current strategies are incapable of eliminating HIV-1 reservoirs and why efforts must focus on eradicating reservoirs to find a future functional cure.

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Rapid Turnover of Effector–Memory CD4+ T Cells in Healthy Humans

Journal of Experimental Medicine ◽

10.1084/jem.20040341 ◽

2004 ◽

Vol 200 (2) ◽

pp. 255-260 ◽

Cited By ~ 131

Author(s):

Derek C. Macallan ◽

Diana Wallace ◽

Yan Zhang ◽

Catherine de Lara ◽

Andrew T. Worth ◽

...

Keyword(s):

T Cells ◽

Cell Population ◽

Cd4 T Cells ◽

Effector Memory ◽

Healthy Humans ◽

In Vivo Labeling ◽

Memory Cd4 T Cells ◽

Doubling Times

Memory T cells can be divided into central–memory (TCM) and effector–memory (TEM) cells, which differ in their functional properties. Although both subpopulations can persist long term, it is not known whether they are maintained by similar mechanisms. We used in vivo labeling with deuterated glucose to measure the turnover of CD4+ T cells in healthy humans. The CD45R0+CCR7− TEM subpopulation was shown to have a rapid proliferation rate of 4.7% per day compared with 1.5% per day for CD45R0+CCR7+ TCM cells; these values are equivalent to average intermitotic (doubling) times of 15 and 48 d, respectively. In contrast, the CD45RA+CCR7+ naive CD4+ T cell population was found to be much longer lived, being labeled at a rate of only 0.2% per day (corresponding to an intermitotic time of approximately 1 yr). These data indicate that human CD4+ TEM cells constitute a short-lived cell population that requires continuous replenishment in vivo.

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CD25+FoxP3+Memory CD4 T Cells Are Frequent Targets of HIV InfectionIn Vivo

Journal of Virology ◽

10.1128/jvi.00612-16 ◽

2016 ◽

Vol 90 (20) ◽

pp. 8954-8967 ◽

Cited By ~ 8

Author(s):

Mkunde Chachage ◽

Georgios Pollakis ◽

Edmund Osei Kuffour ◽

Kerstin Haase ◽

Asli Bauer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Cd4 T Cells ◽

T Cell Subsets ◽

Hiv Dna ◽

Active Viral Replication ◽

Memory Cd4 T Cells

ABSTRACTInterleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replicationin vitroand facilitates homeostatic proliferation of CD25+FoxP3+CD4+T cells. CD25+FoxP3+CD4+T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25+FoxP3+CD4+T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV+and HIV−study volunteers. Different memory CD4+T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV+subjects, 51% (median) of CD25+FoxP3+CD4+T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67+cells were detected in CD25+FoxP3+memory CD4+T cells (median, 27.6%) in comparison to CD25−FoxP3−memory CD4+T cells (median, 4.1%;P< 0.0001). HIV DNA content was 15-fold higher in CD25+FoxP3+memory CD4+T cells than in CD25−FoxP3−T cells (P= 0.003). EnvV1V3 sequences derived from CD25+FoxP3+memory CD4+T cells did not preferentially cluster with plasma-derived sequences. Quasi-identical cell-plasma sequence pairs were rare, and their proportion decreased with the estimated HIV infection duration. These data suggest that specific cellular characteristics of CD25+FoxP3+memory CD4+T cells might facilitate efficient HIV infectionin vivoand passage of HIV DNA to cell progeny in the absence of active viral replication. The contribution of this cell population to plasma virion production remains unclear.IMPORTANCEDespite recent advances in the understanding of AIDS virus pathogenesis, which cell subsets support HIV infection and replicationin vivois incompletely understood.In vitro, the IL-2 signaling pathway and IL-2-dependent cell cycle induction are essential for HIV infection of stimulated T cells. CD25+FoxP3+memory CD4 T cells, often referred to as regulatory CD4 T cells, depend on IL-2 signaling for homeostatic proliferationin vivo. Our results show that CD25+FoxP3+memory CD4+T cells often express the HIV coreceptor CCR5, are significantly more proliferative, and contain more HIV DNA than CD25−FoxP3−memory CD4 T cell subsets. The specific cellular characteristics of CD25+FoxP3+memory CD4+T cells probably facilitate efficient HIV infectionin vivoand passage of HIV DNA to cell progeny in the absence of active viral replication. However, the contribution of this cell subset to plasma viremia remains unclear.

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Endothelial cells promote productive HIV infection of resting CD4+ T cells by an integrin-mediated cell adhesion-dependent mechanism

10.1101/2020.06.29.177402 ◽

2020 ◽

Author(s):

Catherine M. Card ◽

Bernard Abrenica ◽

Lyle R. McKinnon ◽

T. Blake Ball ◽

Ruey-Chyi Su

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Hiv Infection ◽

Cd4 T Cells ◽

Cell Trafficking ◽

Hiv Replication ◽

Hiv Susceptibility ◽

Hiv Acquisition ◽

Memory Cd4 T Cells

AbstractResting CD4+ T cells do not support HIV replication in vitro, yet are primary targets of early HIV infection events in vivo. There is an established role for factors in the tissue microenvironment, including endothelial cells, in enhancing the susceptibility of resting CD4+ T cells to productive infection, yet the mechanisms behind this are not well understood. Endothelial cells facilitate immune cell trafficking throughout the body. Cell adhesion molecules expressed by endothelial cells engage integrins on activated and memory T cells and mediate transmigration into inflamed tissues. These cell trafficking pathways have overlapping roles in facilitating HIV replication but their relevance to endothelial cell-mediated enhancement of HIV susceptibility in resting CD4+ T cells has not previously been examined. We used flow cytometry to characterize the phenotype resting CD4+ T cells that became productively infected when exposed to HIV in the presence of endothelial cells. Infected CD4+ T cells were primarily central memory cells enriched for high expression of the integrins LFA-1 and VLA-4 and had variable expression of α4β7, CCR6 and CD69. Blocking LFA-1 and VLA-4 on resting CD4+ T cells abrogated infection in the co-culture model, indicating that engagement of these integrins is essential for enhancement of resting CD4+ T cell HIV susceptibility by endothelial cells. Cellular activation of CD4+ T cells did not appear to be the primary mechanism enabling HIV replication since only a small proportion of resting CD4+ T cells became activated over the course of the co-culture and fewer than half of infected cells had an activated phenotype. The demonstration that endothelial cells enhance the cellular HIV susceptibility of resting memory CD4+ T cells through cell trafficking pathways engaged during the transmigration of memory T cells into inflamed tissues highlights the physiological relevance of these findings for HIV acquisition and opportunities for intervention.Author SummaryHIV acquisition risk per coital act is relatively low, but this risk is amplified by various behavioural and biological variables. Genital inflammation is a key biological variable associated with increased risk of HIV acquisition, but the mechanisms driving this are incompletely understood. Inflammation is a complex process, with direct effects on HIV target cells as well as the tissue in which those cells reside and encounter virus. The first HIV target cells in vivo are resting memory CD4+ T cells, yet these cells are do not support viral replication when purified and exposed to HIV in vitro. Rather, signals from tissue microenvironment are required to support viral replication within resting memory CD4+ T cells. Endothelial cells line tissue vasculature and guide immune cell trafficking to inflamed tissues through engagement of integrins by endothelial-expressed cell adhesion molecules. We show here that these same cell-trafficking pathways enable endothelial cells to promote HIV replication within resting memory CD4+ T cells in vitro. Blockade of integrins on resting memory CD4+ T cells prevented endothelial enhancement of HIV infection. These findings further our understanding of the determinants of cellular susceptibility to HIV infection and offer a potential mechanism by which inflammation promotes HIV acquisition.

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Antigen Presentation by Human Microvascular Endothelial Cells Triggers ICAM-1-Dependent Transendothelial Protrusion by, and Fractalkine-Dependent Transendothelial Migration of, Effector Memory CD4+ T Cells

The Journal of Immunology ◽

10.4049/jimmunol.180.12.8386 ◽

2008 ◽

Vol 180 (12) ◽

pp. 8386-8392 ◽

Cited By ~ 47

Author(s):

Thomas D. Manes ◽

Jordan S. Pober

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Antigen Presentation ◽

Cd4 T Cells ◽

Transendothelial Migration ◽

Effector Memory ◽

Microvascular Endothelial Cells ◽

Microvascular Endothelial ◽

Memory Cd4 T Cells

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Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood

Journal of Experimental Medicine ◽

10.1084/jem.20130592 ◽

2013 ◽

Vol 210 (9) ◽

pp. 1743-1759 ◽

Cited By ~ 78

Author(s):

Minji Byun ◽

Cindy S. Ma ◽

Arzu Akçay ◽

Vincent Pedergnana ◽

Umaimainthan Palendira ◽

...

Keyword(s):

T Cells ◽

Endothelial Cells ◽

T Cell ◽

Kaposi Sarcoma ◽

Cd4 T Cell ◽

Effector Memory ◽

Activated T Cells ◽

Human Herpes Virus 8

Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)–induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4+ T cells in the peripheral blood, consistent with impaired CD4+ T cell responses to recall antigens in vitro. The proportion of effector memory CD8+ T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4+ T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.

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MAINTENANCE OF MEMORY CD4 CELLS

The Professional Medical Journal ◽

10.29309/tpmj/2014.21.04.2300 ◽

2018 ◽

Vol 21 (04) ◽

pp. 771-781

Author(s):

Mousa Komai Koma

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Memory T Cells ◽

Memory Cell ◽

Tlr2 Agonist ◽

Functional Capacities ◽

Memory Cd4 T Cells

Objective: Ligation of TLR by distinct pathogen components provides essentialsignals for T cell priming, although how individual TLR engagement affects memory T cellsinduction and maintenance in vivo is not well defined. The aim of the present study was toinvestigate the role of TLR2 engagement in the maintenance of memory T cells. Method: Ovaspecific KJ-1 cells from DO-11 mice were adoptively transferred to Balb/c mice. T cells wereactivated with Ova in the host of adoptive cells to induce memory. To examine the function and+ maintenance of memory cells in vivo, CD4 T cells were transferred to mice, which were thenchallenged with Ova-BLP and looked for memory cell proliferation. Furthermore, the memory Tcells harvested from lymph node and spleen of Balb/c mice were treated with Ova and BLP in vitroto establish the effects of TLR2 ligation on proliferation of memory T cells. Two different protocolswere used to confirm the same phenomenon. Results: Two different protocols show thatmemory T cells proliferation in vivo and in vitro can be maintained by TLR2 agonist (BLP). Wedemonstrate that antigen specific CD4 T cells undergo extensive proliferation in the presence ofOva and TLR2 agonist, in fact with TLR2 priming results in greater expansion. Moreover, TLR2agonist priming of ova-specific CD4 T cells resulted in a higher frequency of persisting ova/BLPspecific memory CD4 T cells which facilitated strong secondary responses upon challenge withova antigen. Conclusions: Ligation of TLR2 agonist BLP (Pam3Cys) alone is sufficient to+ maintain the proliferation of Ova specific CD4 T cells without the need of antigen. Which mightsuggest that long-term functional capacities of T cells are set by innate signals during earlyphases of an infection

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Faculty Opinions recommendation of Lifespan of effector memory CD4+ T cells determined by replication-incompetent integrated HIV-1 provirus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718264442.793491515 ◽

2014 ◽

Author(s):

Andrew Badley ◽

Nathan Cummins

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Effector Memory ◽

Memory Cd4 T Cells ◽

Hiv 1

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