The science and medicine of human immunology

Immunology through a human lens The coronavirus disease 2019 (COVID-19) pandemic has underscored the critical need to better understand the human immune system and how to unleash its power to develop vaccines and therapeutics. Much of our knowledge of the immune system has accrued from studies in mice, yet vaccines and drugs that work effectively in mice do not always translate into humans. Pulendran and Davis review recent technological advances that have facilitated the study of the immune system in humans. They discuss new insights and how these can affect the development of drugs and vaccines in the modern era. Science, this issue p. eaay4014 BACKGROUND The mammalian immune system is a remarkable sensory system for the detection and neutralization of pathogens. History is replete with the devastating effects of plagues, and the coronavirus disease 2019 (COVID-19) pandemic is a defining global health crisis of our time. Although the development of effective vaccines has saved many lives, the basic workings of the immune system are complex and require the development of animal models, such as inbred mice. Indeed, research in mice has been enormously productive, and the tremendous insights gleaned have resulted in many Nobel prizes and other accolades. However, past results are not necessarily a reliable guide to the future, and a notable limitation of animal models has been their failure to accurately model some human diseases and their inability to predict human immune responses in many cases. With regard to inbred mice, which have been the principal model of choice for immunology, this is likely due to the compromises that were necessary to create a more tractable and reproducible system for experimentation, such as genetic uniformity and lack of pathogen exposure, as well as the fact that mice are evolutionarily quite distinct. These considerations suggest that direct studies of the human immune system are likely to be extremely rewarding, both from a scientific and a medical perspective. ADVANCES In the past decade there has been an explosion of new approaches and technologies to explore the human immune system with unprecedented precision. Insights into the human immune response to vaccination, cancers, and viral infections such as COVID-19 have come from high-throughput “omics” technologies that measure the behavior of genes, mRNA (single-cell transcriptomics), proteins (proteomics), metabolites (metabolomics), cells (mass cytometry), and epigenetic modifications (ATAC-seq), coupled with computational approaches. OUTLOOK Sydney Brenner remarked in 2008, “We don’t have to look for a model organism anymore. Because we are the model organisms. ” We propose that studying the immune system in humans, who are genetically diverse and afflicted by a multitude of diseases, offers both a direct link to medicine (i.e., “translation”) and the very real prospect of discovering fundamentally new human biology. New approaches and technology are now making this area much more approachable, but profiling immunity in humans is but the first step. Computational mining of the data and biological validation in animal models or human organoids are essential next steps, in an iterative cycle that seeks to bridge fundamental and applied science, as well as mouse and human immunology, in a seamless continuum of scientific discovery and translational medicine. This will represent a new paradigm for accelerating the development of vaccines and therapeutics. Probing the human immune response to viral infections. Systems biology techniques can be used to probe the human immune response to viral infections and can define molecular signatures that predict disease severity and illuminate the underlying mechanisms of disease. ILLUSTRATION: KELLIE HOLOSKI/SCIENCE Although the development of effective vaccines has saved countless lives from infectious diseases, the basic workings of the human immune system are complex and have required the development of animal models, such as inbred mice, to define mechanisms of immunity. More recently, new strategies and technologies have been developed to directly explore the human immune system with unprecedented precision. We discuss how these approaches are advancing our mechanistic understanding of human immunology and are facilitating the development of vaccines and therapeutics for infection, autoimmune diseases, and cancer.