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.
Human immune system variation Brodin, Petter; Davis, Mark M
Nature reviews. Immunology,
01/2017, Volume:
17, Issue:
1
Journal Article
Peer reviewed
Open access
The human immune system is highly variable between individuals but relatively stable over time within a given person. Recent conceptual and technological advances have enabled systems immunology ...analyses, which reveal the composition of immune cells and proteins in populations of healthy individuals. The range of variation and some specific influences that shape an individual's immune system is now becoming clearer. Human immune systems vary as a consequence of heritable and non-heritable influences, but symbiotic and pathogenic microbes and other non-heritable influences explain most of this variation. Understanding when and how such influences shape the human immune system is key for defining metrics of immunological health and understanding the risk of immune-mediated and infectious diseases.
The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. It is now conceivable that an antibody-dependent HIV vaccine might be possible, ...given the discovery of HIV broadly neutralizing antibodies (bnAbs) in some HIV-infected individuals. However, these antibodies are difficult to develop and have characteristics indicative of a high degree of affinity maturation in germinal centers (GCs). CD4+ T follicular helper (Tfh) cells are specialized for B cell help and necessary for GCs. Therefore, the development of HIV bnAbs might depend on Tfh cells. Here, we identified in normal individuals a subpopulation of circulating memory PD-1+CXCR5+CD4+ T cells that are resting memory cells most related to bona fide GC Tfh cells by gene expression profile, cytokine profile, and functional properties. Importantly, the frequency of these cells correlated with the development of bnAbs against HIV in a large cohort of HIV+ individuals.
•PD-1+CXCR5+CD4+ T cells are a population of circulating memory Tfh cells•Optimal Tfh-cell-like function is restricted to PD-1+CXCR3−CXCR5+CD4+ T cells•PD-1+CXCR3−CXCR5+CD4+ T cells correlate with HIV broadly neutralizing antibodies
We have developed a single-molecule imaging technique that uses quantum-dot-labeled peptide-major histocompatibility complex (pMHC) ligands to study CD4+ T cell functional sensitivity. We found that ...naive T cells, T cell blasts, and memory T cells could all be triggered by a single pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of ∼1,000, ∼10,000, and ∼10,000 molecules/min, respectively, and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting T cell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4+ T cell cytokine responses involves increasingly efficient T cell recruitment rather than greater cytokine production per cell.
•Naive, blasting, and memory T cells are equally sensitive to antigenic stimulation•A single pMHC triggers CD4+ T cell cytokine secretion•CD4+ T cell cytokine secretion displays a digital signaling pattern•A single pMHC induces the formation of a TCR cluster
There is considerable heterogeneity in immunological parameters between individuals, but its sources are largely unknown. To assess the relative contribution of heritable versus non-heritable ...factors, we have performed a systems-level analysis of 210 healthy twins between 8 and 82 years of age. We measured 204 different parameters, including cell population frequencies, cytokine responses, and serum proteins, and found that 77% of these are dominated (>50% of variance) and 58% almost completely determined (>80% of variance) by non-heritable influences. In addition, some of these parameters become more variable with age, suggesting the cumulative influence of environmental exposure. Similarly, the serological responses to seasonal influenza vaccination are also determined largely by non-heritable factors, likely due to repeated exposure to different strains. Lastly, in MZ twins discordant for cytomegalovirus infection, more than half of all parameters are affected. These results highlight the largely reactive and adaptive nature of the immune system in healthy individuals.
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•Non-heritable influences explain much of the variation in immune measurements•Immune parameters become more divergent between MZ twins with increasing age•A single non-heritable factor affects more than 50% of all cell subsets and serum proteins•Heritable and non-heritable immune measurements are largely interdependent
An extensive analysis of the immune systems of healthy humans shows that non-heritable factors such as infections, vaccines, and nutrition largely determine immune system variation and that the influence of such non-heritable factors can be both broad and cumulative, overshadowing most heritable influences with time.
While inbred mice have informed most of what we know about the immune system in the modern era, they have clear limitations with respect to their ability to be informative regarding genetic ...heterogeneity or microbial influences. They have also not been very predictive as models of human disease or vaccination results. Although there are concerted attempts to compensate for these flaws, the rapid rise of human studies, driven by both technical and conceptual advances, promises to fill in these gaps, as well as provide direct information about human diseases and vaccination responses. Work on human immunity has already provided important additional perspectives on basic immunology such as the importance of clonal deletion to self-tolerance, and while many challenges remain, it seems inevitable that "the human model" will continue to inform us about the immune system and even allow for the discovery of new mechanisms.
Inbred mice have been an extremely successful tool for basic immunology, but much less so as models of disease. Thus, to maximize the use of immunologic approaches to improve human health, we need ...more strategically directed efforts in human immunology. This would also open up new opportunities for basic research.
CD4
T cells are critical to fighting pathogens, but a comprehensive analysis of human T-cell specificities is hindered by the diversity of HLA alleles (>20,000) and the complexity of many pathogen ...genomes. We previously described GLIPH, an algorithm to cluster T-cell receptors (TCRs) that recognize the same epitope and to predict their HLA restriction, but this method loses efficiency and accuracy when >10,000 TCRs are analyzed. Here we describe an improved algorithm, GLIPH2, that can process millions of TCR sequences. We used GLIPH2 to analyze 19,044 unique TCRβ sequences from 58 individuals latently infected with Mycobacterium tuberculosis (Mtb) and to group them according to their specificity. To identify the epitopes targeted by clusters of Mtb-specific T cells, we carried out a screen of 3,724 distinct proteins covering 95% of Mtb protein-coding genes using artificial antigen-presenting cells (aAPCs) and reporter T cells. We found that at least five PPE (Pro-Pro-Glu) proteins are targets for T-cell recognition in Mtb.
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.
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