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NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing
Anh Thu Dang1, Juliane Strietz2,3, Alessandro Zenobi4
1Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Abstract:
BTN3A molecules-BTN3A1 in particular-emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g. with Mycobacterium tuberculosis, or by alterations in cellular metabolism. Despite the growing interest in the BTN3A genes and their high expression in immune cells and various cancers, little is known about their transcriptional regulation. Here we show that these genes are induced by NLRC5, a regulator of MHC class I gene transcription, through an atypical regulatory motif found in their promoters. Accordingly, a robust correlation between NLRC5 and BTN3A gene expression was found in healthy, in M. tuberculosis-infected donors' blood cells, and in primary tumors. Moreover, forcing NLRC5 expression promoted Vγ9Vδ2 T-cell-mediated killing of tumor cells in a BTN3A-dependent manner. Altogether, these findings indicate that NLRC5 regulates the expression of BTN3A genes and hence open opportunities to modulate antimicrobial and anticancer immunity.
Insights
NLRC5 regulates BTN3A gene expression, crucial for Vγ9Vδ2 T cell activation. This discovery offers new strategies for modulating immune responses against infections and cancers.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- BTN3A molecules, especially BTN3A1, mediate Vγ9Vδ2 T cell activation by phosphoantigens.
- Phosphoantigens can arise from infections like Mycobacterium tuberculosis or metabolic alterations.
- BTN3A genes are highly expressed in immune cells and cancers, yet their transcriptional regulation is poorly understood.
Purpose of the Study:
- To investigate the transcriptional regulation of BTN3A genes.
- To identify the role of NLRC5 in BTN3A gene expression.
- To explore the therapeutic potential of NLRC5-BTN3A axis in immunity.
Main Methods:
- Analysis of promoter regions for regulatory motifs.
- Correlation studies between NLRC5 and BTN3A gene expression in various samples.
- Functional assays assessing Vγ9Vδ2 T cell-mediated killing upon NLRC5 induction.
Main Results:
- NLRC5 induces BTN3A genes via an atypical promoter motif.
- A strong correlation between NLRC5 and BTN3A expression was observed in healthy individuals, M. tuberculosis-infected donors, and tumors.
- Enhanced NLRC5 expression promoted BTN3A-dependent Vγ9Vδ2 T cell killing of tumor cells.
Conclusions:
- NLRC5 is a key regulator of BTN3A gene expression.
- The NLRC5-BTN3A pathway modulates Vγ9Vδ2 T cell responses.
- Targeting this pathway presents opportunities for enhancing antimicrobial and anticancer immunity.
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