Strategies to discover regulatory circuits of the mammalian immune system
Nature reviews. Immunology
Recent advances in technologies for genome-and proteome-scale measurements and perturbations promise to accelerate discovery in every aspect of biology and medicine. Although such rapid technological progress provides a tremendous opportunity, it also demands that we learn how to use these tools effectively. One application with great potential to enhance our understanding of biological systems is the unbiased reconstruction of genetic and molecular networks. Cells of the immune system provide
... particularly useful model for developing and applying such approaches. Here, we review approaches for the reconstruction of signalling and transcriptional networks, with a focus on applications in the mammalian innate immune system. With the rapid development of genomic and proteomic tools, global profiling (BOX 1) of cellular states in terms of gene and protein expression has become a routine activity in immunology. This approach has been used to study T-cell activation signatures 1 , blood cell states in patients with autoimmunity 2 , the responses of host cells to infection 3, 4 and expression patterns that predict vaccine efficacy 5 . Although these datasets have provided important starting points for specific studies of the individual components in these processes, there have been few, if any, attempts to both generate and functionally test the large number of hypotheses that can be derived from genome-scale datasets. Here, we describe systematic functional strategies for the purpose of reconstructing the regulatory networks that underlie any immune process (Fig. 1) . Box 1 Tools of systems immunology Global profiling In this approach, the goal is to measure particular parameters, such as transcript levels or phosphorylated proteins, at the global scale of the entire genome or proteome. Microarrays have been the mainstay of global profiling for more than a decade, but new methods are rapidly shifting the focus towards unbiased sequencing methods that do not depend on predetermined nucleotide probes. These new techniques include transcriptome sequencing by RNA-seq, as well as chromatin immunoprecipitation followed by Correspondence to: I.A., A.R. and N.H.