NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing

Dang, Anh Thu; Strietz, Juliane; Zenobi, Alessandro; Khameneh, Hanif Javanmard; Brandl, Simon M.; Lozza, Laura; Conradt, Gregor; Kaufmann, Stefan H. E.; Reith, Walter; Kwee, Ivo; Minguet, Susana; Chelbi, Sonia T.; Guarda, Greta

doi:10.1016/j.isci.2020.101900

Cited by 20 publications

(18 citation statements)

References 65 publications

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“…In contrast, CRISPR/Cas9-mediated knockout of BTN3A molecules almost eliminated the enhanced lethality induced by NLRC5 overexpressing cells. This new discovery about the relationship between BTN3A family and NLRC5 further discusses the mechanism of BTN3A family in the activation of Vγ9Vδ2 T cells, and brings more implications for the study of immunotherapy 69 .…”

Section: Conclusion and Prospectmentioning

confidence: 84%

Prognostic and Therapeutic Significance of BTN3A Proteins in Tumors

Chen¹,

Li²,

Huang³

et al. 2021

J. Cancer

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The Butyrophilin 3A (BTN3A) family is a type I transmembrane protein belonging to the immunoglobulin (Ig) superfamily. The family contains three members: BTN3A1, BTN3A2 and BTN3A3, which share 95% homology in the extracellular domain. The expression of BTN3A family members is different in different types of tumors, which plays an important role in tumor prognosis. Among them, there are many studies on tumor immunity of BTN3A1, which shows that it is essential for the activation of Vγ9Vδ2 T cells, while BTN3A3 is expected to become a potential therapeutic target for breast cancer. Recent studies have shown that the BTN3A family is closely related to the occurrence and development of tumors. Now the BTN3A family has become one of the research hotspots and is expected to become new tumor prediction and treatment targets.

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Section: Conclusion and Prospectmentioning

confidence: 84%

Prognostic and Therapeutic Significance of BTN3A Proteins in Tumors

Chen¹,

Li²,

Huang³

et al. 2021

J. Cancer

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“…A recent report from the Guarda laboratory has implicated NLRC5 in activating γδ T cells via inducing the expression of butyrophilin (BTN) family proteins BTN3A1-3 [ 175 ]. γδ T cells express TCR with limited diversity that recognize self-MHC proteins in an innate-like fashion independently of their peptide cargo.…”

Section: Induction Of Butyrophilins By Nlrc5 and γδ T Cell Activatmentioning

confidence: 99%

“…The human BTN family genes reside within the MHC locus on chromosome 6 and Btn2a2 is regulated by CIITA via the SXY module [ 179 ]. Guarda and colleagues showed that human BTN3A genes ( BTN3A1 , BTN3A2 , BTN3A3 ) also harbor the SXY module, and their expression positively correlates with NLRC5 [ 175 ]. NLRC5 was shown to bind the promoter region of BTN3A and induce its expression, suggesting a potential role for NLRC5 in immune homeostasis.…”

Section: Induction Of Butyrophilins By Nlrc5 and γδ T Cell Activatmentioning

confidence: 99%

“…Even though crosslinking BTN3A on T cells delivers an inhibitory signal, the impact of high expression of BTN3A in cancer cells on antitumor immunity is not yet clear [ 178 ]. Dang et al, showed that forced expression of NLRC5 in the human Burkitt lymphoma cell line Raji upregulated BTN3A expression and rendered them susceptible to killing by γδ T cells [ 175 ].…”

Section: Induction Of Butyrophilins By Nlrc5 and γδ T Cell Activatmentioning

confidence: 99%

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The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy

Shukla

Cloutier

Santharam

et al. 2021

IJMS

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The immune system constantly monitors the emergence of cancerous cells and eliminates them. CD8+ cytotoxic T lymphocytes (CTLs), which kill tumor cells and provide antitumor immunity, select their targets by recognizing tumor antigenic peptides presented by MHC class-I (MHC-I) molecules. Cancer cells circumvent immune surveillance using diverse strategies. A key mechanism of cancer immune evasion is downregulation of MHC-I and key proteins of the antigen processing and presentation machinery (APM). Even though impaired MHC-I expression in cancers is well-known, reversing the MHC-I defects remains the least advanced area of tumor immunology. The discoveries that NLRC5 is the key transcriptional activator of MHC-I and APM genes, and genetic lesions and epigenetic modifications of NLRC5 are the most common cause of MHC-I defects in cancers, have raised the hopes for restoring MHC-I expression. Here, we provide an overview of cancer immunity mediated by CD8+ T cells and the functions of NLRC5 in MHC-I antigen presentation pathways. We describe the impressive advances made in understanding the regulation of NLRC5 expression, the data supporting the antitumor functions of NLRC5 and a few reports that argue for a pro-tumorigenic role. Finally, we explore the possible avenues of exploiting NLRC5 for cancer immunotherapy.

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“…For the molecular cloning of the pHRSIN-CS-Luc-IRES-mTagBFP2 vector, the previously described pHRSIN-CS-Luc-IRES-emGFP vector (a kind gift from A. Rodriguez, Universidad Autonoma Madrid, Spain) was digested with BstX1 and Not1 restriction enzymes to remove the emGFP. mTagBFP2 was amplified from the previously described pHRSIN-CS-IRES-mTagBFP2 plasmid (Dang et al, 2020) and BstX1-and Not1-specific overhangs were added using PCR. The final expression vector was generated by Gibson assembly using the pHRSIN-CS-Luc-IRES as recipient vector and the amplified mTagBFP2 as insert.…”

Section: Molecular Cloning Of the Luciferase-bfp And S Protein-mscarlet Vectorsmentioning

confidence: 99%

Engineered chimeric T cell receptor fusion construct (TRuC)-expressing T cells prevent translational shutdown in SARS-CoV-2-infected cells

Godbole

Ciminski

Yousefi

et al. 2021

Preprint

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SARS-CoV-2, the causative agent of Covid-19, is known to evade the immune system by several mechanisms. This includes the shutdown of the host cellular protein synthesis, which abrogates the induction of antiviral interferon responses. The virus initiates the infection of susceptible cells by binding with its spike protein (S) to the host angiotensin-converting enzyme 2 (ACE2). Here we applied the T cell receptor fusion construct (TRuC) technology to engineer T cells against such infected cells. In our TRuCs an S-binding domain is fused to the CD3ε component of the T cell receptor (TCR) complex, enabling recognition of S-containing cells in an HLA independent manner. This domain either consists of the S-binding part of ACE2 or a single-chain variable fragment of an anti-S antibody. We show that the TRuC T cells are activated by and kill cells that express S of SARS-CoV-2 and its alpha (B.1.1.7) and beta (B.1.351) variants at the cell surface. Treatment of SARS-CoV-2 infected cells with our engineered T cells did not lead to massive cytotoxicity towards the infected cells, but resulted in a complete rescue of the translational shutdown despite ongoing viral replication. Our data show that engineered TRuC T cell products might be used against SARS-CoV-2 by exposing infected cells to the host innate immune system.

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NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing

Cited by 20 publications

References 65 publications

Prognostic and Therapeutic Significance of BTN3A Proteins in Tumors

Prognostic and Therapeutic Significance of BTN3A Proteins in Tumors

The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy

Engineered chimeric T cell receptor fusion construct (TRuC)-expressing T cells prevent translational shutdown in SARS-CoV-2-infected cells

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