A systems biology approach to target discovery in regulatory T cells

Regulatory T cells (Tregs) have a central role in the maintenance of tolerance to self- antigens and the prevention of autoimmune disease. This study used an integrative systems biology approach to identify tolerogenic genes in Tregs which could potentially serve as novel therapeutic targets for immunological disorders. A consensus Treg gene signature was generated by comparing gene expression in Treg vs naïve or conventional T cells across multiple public studies. Ingenuity Pathway Analysis software was then used to expand the Treg consensus gene list to include interacting proteins accessible to intervention by antibody therapeutics. Many viruses co-opt genes for host proteins that modulate the host’s immune system. It is hypothesized that some viruses may have co-opted genes that can induce tolerance, allowing the virus to evade elimination by the host’s immune system. Putative tolerogenic genes were therefore selected for further investigation based upon their presence in viral genomes. The presence of human genes in viral genomes was investigated by performing a batch reciprocal BLAST search. The biological significance of the human vs viral alignments was evaluated by manual inspection of the alignments and searching for the presence of shared motifs and protein family domains in the viral and human sequences. A final list of ten putative tolerogenic genes included genes known to be associated with immune function and some already established therapeutic targets for autoimmune diseases, as well as four potentially novel therapeutic targets. The biological rationale for the putative targets’ involvement in tolerance was explored in the context of Treg gene expression and protein-protein interaction (PPI) network topology. A PPI network was generated and annotated with confidence scores for each of the interactions. The Cytoscape plugin JActiveModules was used to find putative functional network modules.