Human T cells expressing two additional receptors (TETARs) specific for HIV-1 recognize both epitopes

AbstractAdoptive TCR transfer against rapidly mutating targets, such as HIV-1 or cancer, must counteract corresponding immune escape. Hence, we generated T cells expressing two additional receptors (TETARs) specific for HIV-1 by TCR mRNA electroporation. An HLA-A2–restricted gag-specific TCR and an HLA-B13–restricted nef-specific TCR were chosen. When both TCRs were transfected simultaneously, strong competitive effects occurred that were overcome by replacing the human constant domains of one TCR with murine counterparts and adapting the amounts of TCR-RNA used for transfection. The resulting TETAR responded to both epitopes with cytokine secretion and cytotoxic function. Cell sorting revealed that one individual cell indeed recognized both epitopes. The T cells diminished their reactivity to each epitope after stimulation but sequentially killed targets that presented the gag epitope and then targets that presented the nef epitope, or vice versa. Taken together, TETARs represent a sophisticated tool to study TCR functionality and might be a useful strategy in immunotherapy.

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HIV-1 Selection by Epidermal Dendritic Cells during Transmission across Human Skin

Journal of Experimental Medicine ◽

10.1084/jem.187.10.1623 ◽

1998 ◽

Vol 187 (10) ◽

pp. 1623-1631 ◽

Cited By ~ 129

Author(s):

Jeanette C. Reece ◽

Amanda J. Handley ◽

E. John Anstee ◽

Wayne A. Morrison ◽

Suzanne M. Crowe ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Human Skin ◽

Cell Sorting ◽

Virus Entry ◽

Skin Explants ◽

Skin Uptake ◽

Virus Exposure ◽

Epidermal Dendritic Cells ◽

Hiv 1

Macrophage tropic HIV-1 is predominant during the initial viremia after person to person transmission of HIV-1 (Zhu, T., H. Mo, N. Wang, D.S. Nam, Y. Cao, R.A. Koup, and D.D. Ho. 1993. Science. 261:1179–1181.), and this selection may occur during virus entry and carriage to the lymphoid tissue. Human skin explants were used to model HIV-1 selection that may occur at the skin or mucosal surface. Macrophage tropic, but not T cell line tropic strains of HIV-1 applied to the abraded epidermis were recovered from the cells emigrating from the skin explants. Dermis and epidermis were separated by dispase digestion after virus exposure to determine the site of viral selection within the skin. Uptake and transmission to T cells of all HIV-1 isolates was found with the dermal emigrant cells, but only macrophage tropic virus was transferred by emigrants from the epidermis exposed to HIV-1, indicating selection only within the epidermis. CD3+, CD4+ T cells were found in both the dermal and epidermal emigrant cells. After cell sorting to exclude contaminating T cells, macrophage tropic HIV-1 was found in both the dermal emigrant dendritic cells and in dendritic cells sorted from the epidermal emigrants. These observations suggest that selective infection of the immature epidermal dendritic cells represents the cellular mechanism that limits the initial viremia to HIV-1 that can use the CCR5 coreceptor.

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Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor

Nature Medicine ◽

10.1038/nm.1779 ◽

2008 ◽

Vol 14 (12) ◽

pp. 1390-1395 ◽

Cited By ~ 180

Author(s):

Angel Varela-Rohena ◽

Peter E Molloy ◽

Steven M Dunn ◽

Yi Li ◽

Megan M Suhoski ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Immune Escape ◽

Cell Receptor ◽

Hiv 1

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Disruption of HIV-1 Co-Receptors CCR5 and CXCR4 in Primary Human T Cells and Hematopoietic Stem and Progenitor Cells Using Base Editing

Molecular Therapy ◽

10.1016/j.ymthe.2021.10.026 ◽

2021 ◽

Author(s):

Friederike Knipping ◽

Gregory A. Newby ◽

Cindy R. Eide ◽

Amber N. McElroy ◽

Sarah C. Nielsen ◽

...

Keyword(s):

T Cells ◽

Progenitor Cells ◽

Hematopoietic Stem ◽

Base Editing ◽

Human T Cells ◽

Stem And Progenitor Cells ◽

Hiv 1

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Cooperation between Cancer Cells and Regulatory T Cells to Promote Immune-escape through Integrin αvβ8-Mediated TGF-β Activation

10.21203/rs.3.rs-208701/v1 ◽

2021 ◽

Author(s):

Alexandra Laine ◽

Ossama Labiad ◽

Hector Hernandez-Vargas ◽

Sebastien This ◽

Amélien Sanlaville ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Regulatory T Cells ◽

Cancer Cells ◽

Immune Escape ◽

Antibody Treatment ◽

Inactive Form ◽

Treg Population ◽

Cytotoxic Function ◽

Made In

Abstract Among the strategies allowing cancer cells to escape the immune system, the presence of TGF-b in the tumor micro-environment is one of the most potent. However, TGF-b is secreted in an inactive form and mechanisms responsible for its activation within the tumor remain unknown. Here, we demonstrate that regulatory T cells (Tregs) compose the main cells expressing the b8 chain of avb8 integrin (Itgb8) in the tumors and that the Itgb8pos Treg population activates TGF-b produced by the cancer cells and stored in the tumor micro-environment. Itgb8 ablation in Tregs impaired TGF-b signaling in T lymphocytes present in the tumor but not in the tumor draining lymph nodes. The cytotoxic function of CD8pos T lymphocytes infiltrating the tumors was subsequently exacerbated leading to an efficient control of the tumor growth. Similar observations were made in patient tumors after anti-Itgb8 antibody treatment. Thus, this study reveals that Tregs work in concert with cancer cells to produce bioactive-TGF-b and create a powerful-immunosuppressive micro-environment.

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Potent inhibition of HIV-1 gene expression and TAT-mediated apoptosis in human T cells by novel mono- and multitarget anti-TAT/Rev/Env ribozymes and a general purpose RNA-cleaving DNA-enzyme

Antiviral Research ◽

10.1016/j.antiviral.2006.05.009 ◽

2006 ◽

Vol 72 (2) ◽

pp. 134-144 ◽

Cited By ~ 12

Author(s):

Hoshang Unwalla ◽

Samitabh Chakraborti ◽

Vikas Sood ◽

Nidhi Gupta ◽

Akhil C. Banerjea

Keyword(s):

Gene Expression ◽

T Cells ◽

General Purpose ◽

Human T Cells ◽

Potent Inhibition ◽

Hiv 1

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Synthesis, Characterization and anti-HIV and Antitumor Activities of New Coumarin Derivatives

Zeitschrift für Naturforschung B ◽

10.1515/znb-2008-0112 ◽

2008 ◽

Vol 63 (1) ◽

pp. 83-89 ◽

Cited By ~ 28

Author(s):

Yaseen A. Al-Soud ◽

Haitham H. Al-Sa’doni ◽

Houssain A. S. Amajaour ◽

Kifah S. M. Salih ◽

Mohammad S. Mubarakb ◽

...

Keyword(s):

T Cells ◽

In Vitro Cytotoxicity ◽

Tumor Cell Lines ◽

Coumarin Derivatives ◽

Antitumor Activities ◽

Reverse Transcriptase Inhibitors ◽

Human T Cells ◽

Anti Hiv ◽

Hiv 1

A new series of coumarin and benzofuran derivatives were synthesized as potential non-nucleoside reverse transcriptase inhibitors (NNRTIs) by reacting, separately, 4-bromomethylcoumarins, their sulphonyl chlorides, and ethyl 3-(bromomethyl)-6-methoxy-1-benzofuran-2-carboxylate with different imidazoles and their benzo analogs. The antiviral (HIV-1, HIV-2) properties of the newly synthesized compounds were investigated in vitro and all compounds were found to be inactive, except 10 which showed inhibition of HIV-2 with EC50 > 0.51 μgmL−1. The in vitro cytotoxicity of 17 and 19 was assayed against a panel of tumor cell lines consisting of CD4 human T-cells.

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Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes

Molecular and Cellular Biology ◽

10.1128/mcb.13.10.6180-6189.1993 ◽

1993 ◽

Vol 13 (10) ◽

pp. 6180-6189 ◽

Cited By ~ 6

Author(s):

M H Malim ◽

B R Cullen

Keyword(s):

T Cells ◽

Regulation Of Gene Expression ◽

Nucleocytoplasmic Transport ◽

Viral Mrnas ◽

Nuclear Retention ◽

Human T Cells ◽

Cellular Factors ◽

Immunodeficiency Virus ◽

Nuclear Degradation ◽

Hiv 1

Although a great deal is known about the regulation of gene expression in terms of transcription, relatively little is known about the modulation of pre-mRNA processing. In this study, we exploited a genetically regulated system, human immunodeficiency virus type 1 (HIV-1) and its trans-activator Rev, to examine events that occur between the synthesis of pre-mRNA in the nucleus and the translation of mRNA in the cytoplasm. Unlike the majority of eukaryotic pre-mRNAs whose introns are efficiently recognized and spliced prior to nucleocytoplasmic transport, HIV-1 mRNAs containing functional introns must be exported to the cytoplasm for the expression of many viral proteins. Using human T cells containing stably integrated proviruses, we demonstrate that such incompletely spliced viral mRNAs are exported to the cytoplasm only in the presence of the Rev trans-activator. In the absence of Rev, these intron-containing RNAs are sequestered in the T-cell nucleus and either spliced or, more commonly, degraded. Because Rev does not inhibit the expression of fully spliced viral mRNA species in T cells, we propose that Rev, rather than inhibiting viral pre-mRNA splicing, is acting here both to prevent the nuclear degradation of HIV-1 pre-mRNAs and to induce their translocation to the cytoplasm. Taken together, these findings indicate that the cellular factors responsible for the nuclear retention of unspliced pre-mRNAs, although most probably splicing factors, do not invariably commit these RNAs to productive splicing and can, instead, program such transcripts for degradation.

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