Continuous immunotypes describe human immune variation and predict diverse responses

Abstract

The immune system consists of many specialized cell populations that communicate with each other to achieve systemic immune responses. Our analyses of various measured immune cell population frequencies in healthy humans and their responses to diverse stimuli show that human immune variation is continuous in nature, rather than characterized by discrete groups of similar individuals. We show that the same three key combinations of immune cell population frequencies can define an individual's immunotype and predict a diverse set of functional responses to cytokine stimulation. We find that, even though interindividual variations in specific cell population frequencies can be large, unrelated individuals of younger age have more homogeneous immunotypes than older individuals. Across age groups, cytomegalovirus seropositive individuals displayed immunotypes characteristic of older individuals. The conceptual framework for defining immunotypes suggested by our results could guide the development of better therapies that appropriately modulate collective immunotypes, rather than individual immune components.human immune variation | immune cell composition | systems immunology | aging I n the peripheral blood of humans over 100 different immune cell populations can be distinguished based on the expression of cell surface and intracellular markers. These cell populations span various activation and differentiation states within broader classes of principal immune cell lineages in the adaptive and innate immune systems (1). With recent advances in single-cell measurement technologies such as high-dimensional flow cytometry and mass cytometry (2), these different immune cell populations can be simultaneously quantified in an individual sample. Leveraging these developments, recent population studies have profiled the global immune cell composition in healthy adult humans (3-5) and found these to be highly stable within an individual over the course of weeks to months, but highly variable between individuals (3, 6). Although variations in a few immune cell populations are heritable, the majority of immune cell population frequencies and functional responses are largely determined by nonheritable influences in healthy individuals (4). For example, cohabitation has been shown to be a strong influence, emphasizing the importance of shared environmental factors within a household (6). Most of the specific environmental factors that shape human immune systems have yet to be determined, but monozygotic (MZ) twin pairs discordant for human cytomegalovirus (HCMV) seropositivity were more different in the majority of immune measurements compared with seronegative twins (4).Many studies have focused on individual immune cell populations, their functional properties, regulatory roles, and clinical significance. However, a prototypical immune response involves the coordinated action of multiple cell populations (7, 8), providing both inhibitory and stimulatory feedback, leading to a balanced response that fulfills its protective func...

Human immune system variation during one year

“…In contrast, adult immune systems have previously been shown to be stable over the course of weeks, months and even a few years (Shen-Orr et al, 2016). At the same time, immune system composition in older individuals is more heterogeneous as compared to younger individuals (Kaczorowski et al, 2017) and a recent analysis even use such variability to estimate immunological age that is predictive of all-cause mortality and cardiovascular health (Alpert et al, 2019). Monozygotic twins diverge over time, suggesting a cumulative influence of environmental factors over the course of life shaping human immune systems.…”

“…A comprehensive analysis of immune system variation requires the simultaneous analysis of many cell populations. Because each of these vary substantially among individuals, their collective frequencies are better metrics for accurately describing immune variation than each of the cell frequencies individually (Kaczorowski et al, 2017). We manually gated 115 immune cell populations in each sample, but because these are hierarchical in nature, we only included 53 non-redundant populations for compositional analyses.…”

“…The overall picture remains unclear. At the same time, the variation in blood cell composition is an important issue to understand given that this is a baseline feature that is predictive of a range of functional responses (Kaczorowski et al, 2017) in vitro, but also in vivo (Tsang et al, 2014). Thus, immune cell composition is a potential useful metric of immunological health.…”

Systems-level immunomonitoring using self-sampled capillary blood

“…For example, we have learned in recent years that human immune systems are predominantly shaped by by non-heritable factors such as Cytomegalovirus [2][3][4][5] , and that immune systems diverge with age as environmental exposures accumulate. We are also beginning to learn that baseline immune system states can be predictive of vaccine responses 3,6 , and response to immunomodulatory treatments 7 . During an immune response, for example in the context of immunotherapy of cancer, signatures of immune cell changes can predict clinical outcome 8 .…”

The biology of the cell – insights from mass cytometry

“…This powerful method based on intranuclear staining of histones using metal‐tagged antibodies and analysis by mass cytometry revealed multiple novel chromatin marks differing between individual immune cell populations . Interestingly, the chromatin marks were predominantly driven by nonheritable influences and provide a mechanistic explanation for the previously described divergence of human immune profiles with cumulative environmental exposure over the course of life . The combination of histone marks with other immune cell markers, and even functional response readouts offers another layer of biological regulation to be captured by mass cytometry and promises to shed additional light on the complex regulation within the immune system and other systems consisting of multiple heterogeneous cell populations acting in concert.…”