Volume 22 Issue 10, October 2021

Could we have predicted that the second deadliest pandemic encountered since the influenza pandemic of 1918 would result in the highest mortality and adverse health outcomes among minority and underserved populations in the United States? Given the abundant evidence documenting the disproportionately high burden of preventable disease, disability, and injury among these underserved groups, our answer should echo a resounding ‘yes’.

High-dimensional cytometry experiments measuring 20–50 cellular markers have become routine in many laboratories. The increased complexity of these datasets requires added rigor during the experimental planning and the subsequent manual and computational data analysis to avoid artefacts and misinterpretation of results. Here we discuss pitfalls frequently encountered during high-dimensional cytometry data analysis and aim to provide a basic framework and recommendations for reporting and analyzing these datasets.

Systems approaches applied to human and nonhuman primate cohorts revealed that the transcription factor CREB1 (cAMP-responsive element-binding protein 1) may be a key driver of human immunodeficiency virus 1 vaccine-induced immunity.

Corbett et al. use the rhesus macaque model to evaluate the ability of the mRNA-1273 (Moderna) COVID-19 vaccine to protect against challenge with the antibody-evading Beta variant of SARS-CoV-2. Their key finding is that the vaccine prevents severe lung pathology, principally because it is able to induce a strong enough antibody resistance to overcome the variant’s relative resistance.

Qiu and colleagues identify IRX3 as a driver of macrophage inflammatory cytokines, which can promote metabolic dysfunction.

Type I interferon response to systemic infections after head trauma or stroke impairs angiogenesis in injured tissues and may contribute to secondary neurological injury.

Environmental allergens trigger activation of the ripoptosome in epithelial cells, which mediates the initial allergic response via intracellular processing and release of the alarmin IL-33 and represents a newly identified mechanism for epithelial allergen sensing.

The T helper subset paradigm has been instrumental in informing our understanding of T cell diversity; however, modern single-cell analyses have revealed the limits of the concept. In their Perspective, Becher and colleagues propose an alternative framework in which to understand T helper diversity, based not on transcription factors and cytokines but rather physiological functionality.

Blind mole rats are small rodents characterized by an exceptionally long lifespan and resistance to both spontaneous and induced tumorigenesis. Gorbunova and colleagues show that a transposon-triggered innate immune response confers cancer resistance to the blind mole rat.

Romagnani and colleagues discover an unexpected role for T-bet and RORα during embryonic ILC function and highlight that RORγt is crucial in counteracting the suppressive effects of T-bet.

Fiancette et al. utilize models of inducible transcription factor deletion in mature tissue-resident ILCs to reveal complementary and competing transcriptional networks that determine ILC3 phenotype and functional capacity.

ILCs are considered preformed effector cells. Gasteiger and colleagues report that ILC1s undergo effector differentiation after lineage commitment. Hobit⁺ ILC1s emerge as cKit⁺TCF-1^hi cells that generate tissue-specific helper- and cytotoxic-like cells along a Hobit-dependent trajectory.

Adipose tissue macrophages are intimately involved with adipocytes to orchestrate whole-body energy metabolism. Qiu and colleagues show that myeloid-specific deletion of the homeobox protein IRX3 protects against diet-induced obesity, excessive proinflammatory cytokine secretion and metabolic diseases via increasing adaptive thermogenesis.

Traumatic brain injury and stroke are commonly complicated by systemic infections, which impede recovery and lead to poor clinical outcomes. Using a mouse model, McGavern and colleagues show systemic microbial infections impair central nervous system revascularization and repair by a mechanism involving type I interferon signaling.

Understanding the mechanistic basis of vaccine efficacy is crucial to the development of next-generation vaccines. Sekaly and colleagues find that activation of the transcription factor CREB1 by the RV144 HIV-1 vaccine underpins the induction of robust adaptive immunity.

The beta variant (B.1.351) is to date the most resistant to neutralization of the SARS-CoV-2 variants. Using nonhuman primates, Seder and colleagues demonstrate that double vaccination with a high dose of the lipid nanoparticle vaccine mRNA-1273 protects against infection with the beta variant.

IL-33 plays a central role in type II immune responses and is generally thought to be released following cellular damage and processed extracellularly. Rothenberg and colleagues describe a new ripoptosome pathway that is assembled following exposure to various unrelated environmental allergens and that processes IL-33 into an active form intracellularly.

Elemento, Melnick and colleagues examine the chromatin and transcriptional changes that occur during differentiation of human primary B cells into antibody-secreting cells. In naive B cells, the transcription factor OCT2 is preloaded at high-affinity super-enhancer sites present in repressed ‘silent’ chromatin; upon activation, OCAB is recruited to these regions, where it facilitates arrays of OCT2 binding to lower-affinity octamer motifs, leading to active formation of germinal center B cell-specific super-enhancers.