Transcription factor GATA-1 potently represses the expression of the HIV-1 coreceptor CCR5 in human T cells and dendritic cells

AbstractCC chemokine receptor 5 (CCR5) is the major HIV-1 coreceptor and its expression levels are a critical determinant of HIV-1 infection. However, the molecular mechanisms of CCR5 regulation in primary targets of HIV-1 remain unknown. Despite binding to conserved DNA elements, we show that the transcription factors GATA binding protein 1 (GATA-1) and GATA-3 differentially suppress the expression of CCR5 in stem-cell–derived dendritic cells and primary human T-cell subsets. In addition, GATA-1 expression was also more potent than GATA-3 in suppressing T helper 1 (Th1)–associated genes, interferon-γ (IFNγ), and CXC chemokine receptor-3 (CXCR3). GATA-1, but not GATA-3, potently suppressed CCR5 transcription, thereby rendering human T cells resistant to CCR5-tropic HIV-1 infection. However, GATA-1 could also serve as a surrogate for GATA-3 in its canonic role of programming Th2 gene expression. These findings provide insight into GATA-3–mediated gene regulation during T-cell differentiation. Importantly, decoding the mechanisms of GATA-1–mediated repression of CCR5 may offer an opportunity to develop novel approaches to inhibit CCR5 expression in T cells.

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IL-8 responsiveness defines a subset of CD8 T cells poised to kill

Blood ◽

10.1182/blood-2004-03-1067 ◽

2004 ◽

Vol 104 (12) ◽

pp. 3463-3471 ◽

Cited By ~ 56

Author(s):

Christoph Hess ◽

Terry K. Means ◽

Patrick Autissier ◽

Tonia Woodberry ◽

Marcus Altfeld ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Chemokine Receptor ◽

Cd8 T Cells ◽

Molecular Mechanisms ◽

Cell Subset ◽

Cd8 T Cell ◽

Effector Memory ◽

Immune System Activation ◽

Hiv 1

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)–responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-γ (IFNγ), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1–specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.

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Cure of disseminated xenografted human Hodgkin's tumors by bispecific monoclonal antibodies and human T cells: the role of human T-cell subsets in a preclinical model

Blood ◽

10.1182/blood.v87.7.2930.bloodjournal8772930 ◽

1996 ◽

Vol 87 (7) ◽

pp. 2930-2937 ◽

Cited By ~ 24

Author(s):

C Renner ◽

S Bauer ◽

U Sahin ◽

W Jung ◽

R van Lier ◽

...

Keyword(s):

T Cells ◽

Monoclonal Antibodies ◽

T Cell ◽

Hodgkin's Disease ◽

Hodgkin’S Disease ◽

Scid Mice ◽

T Cell Subsets ◽

Human T Cell ◽

Human T Cells

Cure of a single established human Hodgkin's tumor growing subcutaneously in severe combined immunodeficient (SCID) mice can be achieved with a complex protocol using two bispecific monoclonal antibodies (Bi-MoAb) directed against the Hodgkin's associated CD30 antigen and the T-cell triggering molecules CD3 and CD28, respectively, together with human T cells prestimulated in vitro with Bi-MoAbs in the presence of CD30+ cells. To adapt this model to the clinical situation, disseminated tumors were established in SCID mice by intravenous injection of 2 x 10(7) cells of the Hodgkin's derived cell line L540CY. Treatment of SCID mice bearing disseminated CD30+ Hodgkin's tumors with the combination of CD3/CD30 and CD28/CD30 Bi-MoAbs and naive (ie, not in vitro prestimulated) human T cells resulted in the cure of all appropriately treated animals. T lymphocytes obtained from patients with advanced stage untreated Hodgkin's disease were as effective as lymphocytes from healthy controls. Treatment was effective even when delayed until 2 weeks after tumor inoculation, and application of Bi- MoAbs into SCID mice with circulating human T cells was as effective as injecting the Bi-MoAbs before the lymphocytes. Treatment results with isolated CD4+ and CD8+ human T cells suggest that both subsets are necessary for the Bi-MoAb mediated cure of xenografted human tumors in vivo. The efficacy and practicability of this preclinical immunotherapy protocol support and form the basis for the clinical evaluation of this approach in patients with Hodgkin's disease resistant to standard therapy.

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In Vitro Priming of Human T Cells by Dendritic Cells Provides a Screening Tool for Candidate Vaccines for Burkholderia pseudomallei

Vaccines ◽

10.3390/vaccines9080929 ◽

2021 ◽

Vol 9 (8) ◽

pp. 929

Author(s):

Durga Reddi ◽

Lydia Durant ◽

David Bernardo ◽

Alistair Noble ◽

Nicholas R. English ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Burkholderia Pseudomallei ◽

Cellular Response ◽

Ex Vivo ◽

Cell Mediated Immunity ◽

Human T Cell ◽

Human T Cells

Murine dendritic cells, when pulsed with heat-killed Burkholderia pseudomallei and used to immunise naïve mice, have previously been shown to induce protective immunity in vivo. We have now demonstrated the in vitro priming of naïve human T cells against heat-killed B. pseudomallei, by co-culture with syngeneic B. pseudomallei-pulsed dendritic cells. Additionally, we have enriched the DC fraction such that a study of the differential response induced by pulsed DCs of either myeloid or plasmacytoid lineage in syngeneic human T cells was achievable. Whilst both mDCs and pDCs were activated by pulsing, the mDCs contributed the major response to B. pseudomallei with the expression of the migration marker CCR7 and a significantly greater secretion of the proinflammatory TNFα and IL1β. When these DC factions were combined and used to prime syngeneic T cells, a significant proliferation was observed in the CD4+ fraction. Here, we have achieved human T cell priming in vitro with unadjuvanted B. pseudomallei, the causative organism of melioidosis, for which there is currently no approved vaccine. We propose that the approach we have taken could be used to screen for the human cellular response to candidate vaccines and formulations, in order to enhance the cell-mediated immunity required to protect against this intracellular pathogen and potentially more broadly against other, difficult-to-treat intracellular pathogens. To date, the polysaccharide capsule of B. pseudomallei, fused to a standard carrier protein, e.g., Crm, looks a likely vaccine candidate. Dendritic cells (DCs), providing, as they do, the first line of defence to infection, process and present microbial products to the immune system to direct downstream immune responses. Here, we have sought to use DCs ex vivo to identify immunogenic products from heat-killed B. pseudomallei. Using practical volumes of fresh human donor blood, we show that heat-killed B. pseudomallei activated and stimulated the expression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 from both myeloid and plasmacytoid DCs. Furthermore, B. pseudomallei-pulsed DCs cultured with naïve syngeneic T cells ex vivo, induced the activation and proliferation of the CD4+ T-cell population, which was identified by cell surface marker staining using flow cytometry. Thus, both DC subsets are important for driving primary T helper cell responses to B. pseudomallei in healthy individuals and have the potential to be used to identify immunogenic components of B. pseudomallei for future therapies and vaccines.

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B Lymphocytes, but Not Dendritic Cells, Efficiently HIV-1 Trans Infect Naive CD4+ T Cells: Implications for the Viral Reservoir

mBio ◽

10.1128/mbio.02998-20 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Abigail Gerberick ◽

Diana C. DeLucia ◽

Paolo Piazza ◽

Mounia Alaoui-El-Azher ◽

Charles R. Rinaldo ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

B Lymphocytes ◽

T Cell Subsets ◽

Viral Reservoir ◽

Myeloid Dendritic Cells ◽

And Control ◽

Hiv 1

ABSTRACT Insight into the establishment and maintenance of HIV-1 infection in resting CD4+ T cell subsets is critical for the development of therapeutics targeting the HIV-1 reservoir. Although the frequency of HIV-1 infection, as quantified by the frequency of HIV-1 DNA, is lower in CD4+ naive T cells (TN) than in the memory T cell subsets, recent studies have shown that TN harbor a large pool of replication-competent virus. Interestingly, however, TN are highly resistant to direct (cis) HIV-1 infection in vitro, in particular to R5-tropic HIV-1, as TN do not express CCR5. In this study, we investigated whether TN could be efficiently HIV-1 trans infected by professional antigen-presenting B lymphocytes and myeloid dendritic cells (DC) in the absence of global T cell activation. We found that B cells, but not DC, have a unique ability to efficiently trans infect TN in vitro. In contrast, both B cells and DC mediated HIV-1 trans infection of memory and activated CD4+ T cells. Moreover, we found that TN isolated from HIV-1-infected nonprogressors (NP) harbor significantly disproportionately lower levels of HIV-1 DNA than TN isolated from progressors. This is consistent with our previous finding that antigen-presenting cells (APC) derived from NP do not efficiently trans infect CD4+ T cells due to alterations in APC cholesterol metabolism and cell membrane lipid raft organization. These findings support that B cell-mediated trans infection of TN with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. IMPORTANCE The latent human immunodeficiency virus type 1 (HIV-1) reservoir in persons on antiretroviral therapy (ART) represents a major barrier to a cure. Although most studies have focused on the HIV-1 reservoir in the memory T cell subset, replication-competent HIV-1 has been isolated from TN, and CCR5-tropic HIV-1 has been recovered from CCR5neg TN from ART-suppressed HIV-1-infected individuals. In this study, we showed that CCR5neg TN are efficiently trans infected with R5-tropic HIV-1 by B lymphocytes, but not by myeloid dendritic cells. Furthermore, we found that TN isolated from NP harbor no or significantly fewer copies of HIV-1 DNA than those from ART-suppressed progressors. These findings support that B cell-mediated trans infection of TN with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. Understanding the establishment and maintenance of the HIV-1 latent reservoir is fundamental for the design of effective treatments for viral eradication.

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B LYMPHOCYTES, BUT NOT DENDRITIC CELLS, EFFICIENTLY HIV-1 TRANS-INFECT NAÏVE CD4+ T CELLS: IMPLICATIONS FOR THE VIRAL RESERVOIR

10.1101/2020.10.22.351627 ◽

2020 ◽

Author(s):

Abigail Gerberick ◽

Diana C. DeLucia ◽

Paolo Piazza ◽

Mounia Alaoui-El-Azher ◽

Charles R. Rinaldo ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

B Lymphocytes ◽

T Cell Subsets ◽

Viral Reservoir ◽

Myeloid Dendritic Cells ◽

And Control ◽

Hiv 1

AbstractInsight into the establishment and maintenance of HIV-1 infection in resting CD4+ T cell subsets is critical for the development of therapeutics targeting the HIV-1 reservoir. Although the frequency of HIV-1 infection, as quantified by the frequency of HIV-1 DNA, is lower in CD4+ naïve T cells (TN) compared to the memory T cell subsets, recent studies have shown that TN cells harbor a large pool of replication-competent virus. Interestingly, however, TN cells are highly resistant to direct (cis) HIV-1 infection in vitro, in particular to R5-tropic HIV-1, as TN cells do not express CCR5. In this study, we investigated whether TN cells could be efficiently HIV-1 trans-infected by professional antigen-presenting B lymphocytes and myeloid dendritic cells (DC) in the absence of global T cell activation. We found that B cells, but not DC, have a unique ability to efficiently trans infect TN cells in vitro. In contrast, both B cells and DC mediated HIV-1 trans infection of memory and activated CD4+ T cells. Moreover, we found that TN isolated from HIV-1-infected nonprogressors (NP) harbor significantly disproportionately lower levels of HIV-1 DNA compared to TN isolated from progressors. This is consistent with our previous finding that APC derived from NP do not efficiently trans-infect CD4+ T cells due to alterations in APC cholesterol metabolism and cell membrane lipid raft organization. These findings support that B cell-mediated trans infection of TN cells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression.ImportanceThe latent human immunodeficiency virus type 1 (HIV-1) reservoir in persons on antiretroviral therapy represents a major barrier to a cure. Although most studies have focused on the HIV-1 reservoir in the memory T cell subset, replication competent HIV-1 has been isolated from naïve T cells, and CCR5-tropic HIV-1 has been recovered from CCR5negTN cells from ART-suppressed HIV-1-infected individuals. In this study, we showed that CCR5negTN cells are efficiently trans infected with R-5 tropic HIV-1 by B lymphocytes, but not by myeloid dendritic cells. Furthermore, we found that TN isolated from NP harbor no or significantly less copies of HIV-1 DNA compared to ART-suppressed progressors. These findings support that B cell-mediated trans infection of TN cells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. Understanding the establishment and maintenance of the HIV-1 latent reservoir is fundamental for the design of effective treatments for viral eradication.

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Synthetic mycobacterial diacyl trehaloses reveal differential recognition by human T cell receptors and the C-type lectin Mincle

Scientific Reports ◽

10.1038/s41598-021-81474-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Josephine F. Reijneveld ◽

Mira Holzheimer ◽

David C. Young ◽

Kattya Lopez ◽

Sara Suliman ◽

...

Keyword(s):

T Cells ◽

Fatty Acid ◽

Immune System ◽

T Cell ◽

Cross Reactivity ◽

Lipid Binding ◽

Human Immune System ◽

Human T Cell ◽

Human T Cells ◽

Pure Compounds

AbstractThe cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three forms of mycobacterial diacyltrehalose (DAT) that differ in their fatty acid composition, DAT1, DAT2, and DAT3. To study the potential recognition of DATs by human T cells, we treated the lipid-binding antigen presenting molecule CD1b with synthetic DATs and looked for T cells that bound the complex. DAT1- and DAT2-treated CD1b tetramers were recognized by T cells, but DAT3-treated CD1b tetramers were not. A T cell line derived using CD1b-DAT2 tetramers showed that there is no cross-reactivity between DATs in an IFN-γ release assay, suggesting that the chemical structure of the fatty acid at the 3-position determines recognition by T cells. In contrast with the lack of recognition of DAT3 by human T cells, DAT3, but not DAT1 or DAT2, activates Mincle. Thus, we show that the mycobacterial lipid DAT can be both an antigen for T cells and an agonist for the innate Mincle receptor, and that small chemical differences determine recognition by different parts of the immune system.

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Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells

Mediators of Inflammation ◽

10.1155/2014/738631 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Song Chen ◽

Ran Ding ◽

Yan Zhou ◽

Xian Zhang ◽

Rui Zhu ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Molecular Mechanisms ◽

Interleukin 12 ◽

Related Factors ◽

Knock Out ◽

Specific Immunity

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.

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Susceptibility of human T cells, T-cell subsets, and B cells to cryopreservation

Cryobiology ◽

10.1016/0011-2240(86)90045-3 ◽

1986 ◽

Vol 23 (3) ◽

pp. 199-208 ◽

Cited By ~ 11

Author(s):

M. Venkataraman ◽

M.P. Westerman

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

T Cell Subsets ◽

Human T Cells

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Generation of primary antigen-specific human cytotoxic T lymphocytes in human/mouse radiation chimera

Blood ◽

10.1182/blood.v88.2.721.bloodjournal882721 ◽

1996 ◽

Vol 88 (2) ◽

pp. 721-730 ◽

Cited By ~ 30

Author(s):

H Segall ◽

I Lubin ◽

H Marcus ◽

A Canaan ◽

Y Reisner

Keyword(s):

T Cells ◽

T Cell ◽

Human Lymphocytes ◽

Scid Mice ◽

Human Antibody ◽

Adoptive Therapy ◽

Activation Markers ◽

Human T Cell ◽

Human T Cells

Severe combined immunodeficient (SCID) mice are increasingly used as hosts for the adoptive transfer of human lymphocytes. Human antibody responses can be obtained in these xenogeneic chimeras, but information about the functionality of the human T cells in SCID mice is limited and controversial. Studies using human peripheral blood lymphocytes (PBL) injected intraperitoneally (IP) into SCID mice (hu-PBL-SCID mice) have shown that human T cells from these chimeras are anergic and have a defective signaling via the T-cell receptor. In addition, their antigenic repertoire is limited to xenoreactive clones. In the present study, we tested the functionality of human T cell in a recently described chimeric model. In this system, BALB/c mice are conditioned by irradiation and then transplanted with SCID bone marrow, followed by IP injection of human PBL. Our experiments demonstrated that human T cells, recovered from these hu-PBL-BALB mice within 1 month posttransplant, proliferated and expressed activation markers upon stimulation with anti-CD3 monoclonal antibody. A vigorous antiallogeneic human cytotoxic T-lymphocyte (CTL) response could be generated in these mice by immunizing them with irradiated allogeneic cells. Moreover, anti-human immunodeficiency virus type 1 (HIV-1) Net- specific human CTLs could be generated in vivo from naive lymphocytes by immunization of mouse-human chimeras with a recombinant vaccinia-nef virus. This model may be used to evaluate potential immunomodulatory drugs or cytokines, and could provide a relevant model for testing HIV vaccines, for production of antiviral T-cell clones for adoptive therapy, and for studying human T-cell responses in vivo.

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Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease

Nature Communications ◽

10.1038/s41467-019-12464-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 54

Author(s):

Peter A. Szabo ◽

Hanna Mendes Levitin ◽

Michelle Miron ◽

Mark E. Snyder ◽

Takashi Senda ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Single Cell ◽

T Cell Activation ◽

Cell Activation ◽

Interferon Response ◽

Functional Responses ◽

Multiple Tumor ◽

Human T Cell ◽

Human T Cells

Abstract Human T cells coordinate adaptive immunity in diverse anatomic compartments through production of cytokines and effector molecules, but it is unclear how tissue site influences T cell persistence and function. Here, we use single cell RNA-sequencing (scRNA-seq) to define the heterogeneity of human T cells isolated from lungs, lymph nodes, bone marrow and blood, and their functional responses following stimulation. Through analysis of >50,000 resting and activated T cells, we reveal tissue T cell signatures in mucosal and lymphoid sites, and lineage-specific activation states across all sites including distinct effector states for CD8+ T cells and an interferon-response state for CD4+ T cells. Comparing scRNA-seq profiles of tumor-associated T cells to our dataset reveals predominant activated CD8+ compared to CD4+ T cell states within multiple tumor types. Our results therefore establish a high dimensional reference map of human T cell activation in health for analyzing T cells in disease.

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