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Published on: January 22, 2019
BTLA and PD-1 signals attenuate TCR-mediated transcriptomic changes
Muhammad Zainul Arifin1, Judith Leitner2, Donagh Egan1
1Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Abstract:
T cell co-inhibitory immune checkpoints, such as PD-1 or BTLA, are bona fide targets in cancer therapy. We used a human T cell reporter line to measure transcriptomic changes mediated by PD-1- and BTLA-induced signaling. T cell receptor (TCR)-complex stimulation resulted in the upregulation of a large number of genes but also in repression of a similar number of genes. PD-1 and BTLA signals attenuated transcriptomic changes mediated by TCR-complex signaling: upregulated genes tended to be suppressed and the expression of a significant number of downregulated genes was higher during PD-1 or BTLA signaling. BTLA was a significantly stronger attenuator of TCR-complex-induced transcriptome changes than PD-1. A strong overlap between genes that were regulated indicated quantitative rather than qualitative differences between these receptors. In line with their function as attenuators of TCR-complex-mediated changes, we found strongly regulated genes to be prime targets of PD-1 and BTLA signaling.
Insights
Immune checkpoints like PD-1 and BTLA dampen T cell receptor signaling. BTLA more strongly suppresses gene expression changes than PD-1, highlighting their role in cancer therapy.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Therapy
Background:
- Immune checkpoints, including PD-1 and BTLA, are crucial targets in cancer immunotherapy.
- T cell receptor (TCR) signaling orchestrates significant transcriptomic alterations.
Purpose of the Study:
- To investigate the transcriptomic modifications induced by PD-1 and BTLA signaling in human T cells.
- To compare the attenuating effects of PD-1 and BTLA on TCR-mediated gene expression.
Main Methods:
- Utilized a human T cell reporter line to monitor gene expression changes.
- Analyzed transcriptomic profiles following TCR-complex stimulation alone and in combination with PD-1 or BTLA signaling.
Main Results:
- TCR stimulation led to both gene upregulation and repression.
- PD-1 and BTLA signaling attenuated TCR-induced transcriptomic changes, suppressing upregulated genes and increasing expression of downregulated genes.
- BTLA demonstrated a stronger attenuating effect than PD-1.
- Significant overlap in regulated genes suggests quantitative differences between PD-1 and BTLA.
Conclusions:
- PD-1 and BTLA act as negative regulators of TCR-mediated transcriptomic responses.
- The findings underscore the role of these immune checkpoints in modulating T cell activation and provide insights for cancer therapy strategies.
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