Rohit Bhattacharjee, Amity University Kolkata
Although inhibition of T cell co-inhibitory receptors has brought about cancer therapy, mechanisms governing their expression on human T cells have not been explained. Type 1 interferon (IFN-I) regulates T cell immunity in viral infection, autoimmunity, cancer, and may enhance induction of T cell exhaustion in chronic viral infection. To enable the construction of dynamic transcriptional regulatory networks high-temporal resolution mRNA profiling of IFN-I responses were done to uncover three temporal transcriptional waves.
After disturbance of the key transcription factors on human primary T cells, it revealed both canonical and non-canonical IFN-I transcriptional regulators and recognised unique regulators controlling the expression of co-inhibitory receptors. To provide direct in vivo evidence for the role of IFN-I on co-inhibitory receptors, single-cell RNA-sequencing in subjects infected with SARS-CoV-2 was performed, where the viral load was strongly associated with T cell Type 1 Interferon (IFN-I) signatures. It was found out that the dynamic IFN-I response in vitro closely mimicked T cell characteristics with acute IFN-I linked viral infection, having high LAG3 and low TIGIT expression.
Lastly, the gene regulatory network identified SP140 as a key regulator for differential LAG3 and TIGIT expression. The construction of IFN-I induced co-inhibitory regulatory networks with identification of unique transcriptional factors controlling their expression may provide targets for enhancement of cancer immunotherapy, infectious diseases, and autoimmunity. Conclusively, this approach identifies the cytokine signals and regulatory mechanisms driving the expression of humans’ co-inhibitory receptors, providing a pathway to comprehensively capture the dynamics of their human expressions.
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Source:- McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol 37, 457-495, doi:10.1146/annurev-Immunol-041015-055318 (2019).https://www.biorxiv.org/content/10.1101/2020.10.30.362947v1
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