Systems immunology: just getting started

Abstract

Systems-biology approaches in immunology take various forms, but here we review strategies for measuring a broad swath of immunological functions as a means of discovering previously unknown relationships and phenomena and as a powerful way of understanding the immune system as a whole. This approach has rejuvenated the field of vaccine development and has fostered hope that new ways will be found to combat infectious diseases that have proven refractory to classical approaches. Systems immunology also presents an important new strategy for understanding human immunity directly, taking advantage of the many ways the immune system of humans can be manipulated.

Figure 1

Tools of the trade: a systems-immunology view. Investigating the immune system can be accomplished with a variety of techniques applied to the analysis of peripheral blood samples obtained from healthy donors, as well as those obtained at specific time points during infection, disease or after vaccination. Innate cell subsets can be characterized by RNA-seq, flow cytometry, cytometry by time-of-flight (CyTOF) and flow cytometry of phosphorylated proteins (Phospho-flow) to reveal mediators of early inflammation, and their signaling pathways (a). Cells can be classified by phenotype and functional capacity on the basis of a variety of cell-surface markers and receptor expression. Effector proteins, such as cytokines and cytolytic granules, along with other products of activated cells, can be detected intracellularly by flow cytometry or in the serum with other methodologies, such as bead-based multiplex assays (Luminex) or immunoassay kits (from Mesoscale Discovery), to rapidly survey more than 100 analytes in a single, small sample (b). Cell subsets of the adaptive immune system can be investigated for antigen specificity by tetramer technology and mass spectrometry to explore peptide presentation, as well as sequencing of the TCR and BCR repertoire for the identification of clonally expanded populations. Furthermore, antibody-repertoire sequencing can be used to characterize the extent of isotype class switching and affinity maturation (c). Many of these techniques are currently being adapted for the analysis of smaller tissue-biopsy samples to extract information about the local inflammatory environment and the infiltrating cell populations (d). s APC, antigen-presenting cell; T_H, helper T cell; B, B cell; CD4, CD4+ T cell; NK, natural killer cell; γδ, γδ T cell; T, T cell; ICS, intracellular cytokine staining; CD8, CD8⁺ T cell; CTL, cytotoxic T lymphocyte.

Figure 2

The ideal team. Cross-disciplinary efforts have allowed considerable advances in human medical research. The integration of clinical research (a) was made possible by the invention of new technologies (b) for comprehensive analysis of precious blood and tissue samples. The development of new algorithms for the visualization and analysis of such large data sets (c) has enabled novel insights and the generation of new hypotheses (d). Such collaborations should help to bridge the gap between bench and bedside by accelerating the translational pipeline (e).

Figure 3

A comprehensive picture of health. The immune system has a fundamental role in a variety of diseases and disorders, including the capacity for resistance, recovery and maintenance of the health of a person.