Bioinformatics Seminar
Time:
Venue: Na
17 April 2018
NaBioinformatics analyses to uncover the molecular mechanism underlying T cell exhaustion caused by chronic infection
Yang LiaoWEHI Bioinformatics
Immune T cell exhaustion has been known as a result of persistent antigenic stimulation in chronic infection or cancer. Although T cell exhaustion is known to impair the ability of the immune system in clearing the antigen and prolong the course of infection ; very little is known about the molecular mechanism underlying the initiation and maintenance of T cell exhaustion.
In this talk ; I will present the bioinformatics analyses we carried out to try to understand the transcriptome changes and gene regulation that occurred during the process of T cell exhaustion. Using RNA-seq data generated from CD8+ T cells that were harvested from samples with acute or chronic viral infections ; we identified a gene signature that characterizes the development of T cell exhaustion. We found that many of the signature genes are regulated by a master transcription factor ; Irf4. The analysis of ChIP-seq data revealed that Irf4 binds to many of these signature genes and therefore directly regulates their expression. We further investigated the role of two other important transcription factors ; Batf and Nfatc1 ; in regulating the expression of genes implicated in T cell exhaustion arising from chronic infection. A large portion of chronic signature genes were found to be transcriptionally bound by all three factors ; manifesting the cooperative activity of these factors in establishing T cell exhaustion. The close proximity between the binding sites from different factors further signified the cooperation of the three factors. The genome-wide analysis of expression changes and transcription factor binding in samples with chronic infection suggests that T cell exhaustion is potentially established and maintained by a transcriptional network comprising transcription factors including Irf4 ; Batf and Nfatc1. Key genes identified from this study are potential therapeutic targets for improved diagnosis and treatment of patients with chronic infection.