Perspectives

Here, Lipsitch and colleagues assess the impact of breakthrough SARS-CoV-2 infections that occur in individuals who have been vaccinated against COVID-19. The authors explain how the rate of breakthrough infections can be measured, what the causes of these infections are and discuss other key questions that need to be considered in light of these infections.

In this Perspective, Lok-Yin Roy Wong and Stanley Perlman consider how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses are able to drive immune dysregulation and immunopathology. They provide an overview of the coronavirus-derived molecules that interfere with key innate immune responses, including interferon pathways and complement, NF-κB signalling and inflammasome activation, as well as with the activation of host adaptive immunity.

This Perspective chronicles the journey to the elimination of transmission of wild poliovirus in Africa, with a critical discussion of the global, continental, national and community actions that were required and the lessons learnt along the way.

In this Perspective, the authors propose that innate immune detection of oxidized phospholipids, which result from tissue injury, allows the immune system to assess the degree of danger; the detection of oxidized phosphocholines in the presence of pathogen-associated molecular patterns or damage-associated molecular patterns triggers a heightened immune response.

In this Perspective, McInnes and Gravallese highlight the remarkable progress made over the past 20 years in treating immune-mediated inflammatory diseases. The available therapies have progressed from broad-spectrum immune modulators to highly targeted biological and small-molecule agents as our understanding of disease mechanisms has advanced.

In this Perspective, Murphy and Febbraio reflect on the advances that have been made in the past 20 years in developing therapies for cardiovascular and metabolic diseases that target the immune system. They also consider the potential of emerging immune-based therapies for these diseases.

Phase separation has emerged as a new biophysical principle for organizing biomolecules into large clusters with fluidic properties. Here, Su and colleagues summarize what we currently know about phase separation in immune cells and look to the future of this field in understanding the regulation of immune signalling.

Emerging diseases that affect humans often arise due to the crossover of infectious agents from animal reservoirs. In this Perspective, George Warimwe and colleagues discuss the concept of ‘One Health vaccinology’, an approach that aims to use key lessons from human and veterinary immunology to develop more effective vaccination strategies for emerging infectious diseases.

The duration of immunity to coronavirus disease 2019 (COVID-19) from prior infection and longer-term risk of reinfection are currently unclear. Cromer and colleagues discuss the immune control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the implications of this for the future control of the pandemic.

Here, the authors propose that SARS-CoV-2 induces a prothrombotic state, with dysregulated immunothrombosis in lung microvessels and endothelial injury, which drive the clinical manifestations of severe COVID-19. They discuss potential antithrombotic and immunomodulating drugs that are being considered in the treatment of patients with COVID-19.

In this Perspective, Cobey, Larremore, Grad and Lipsitch argue that dose-sparing regimens of COVID-19 vaccines can reduce disease incidence, prevalence and burden and explain why they think that such strategies would also slow the rate of viral escape from vaccine or naturally induced immunity.

A timeline of the major scientific discoveries during the first year of the COVID-19 pandemic showcases the collaborative efforts that enabled the key aspects of the immune response to SARS-CoV-2 to be reported at unprecedented speed.

In this Perspective, Alon and colleagues discuss how insights into immune cell trafficking during pneumotropic influenza virus infections may inform our understanding of immune cell recruitment to the respiratory tract in patients with coronavirus disease 2019 (COVID-19). Moreover, they examine the emerging knowledge of vascular pathologies beyond the lung caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

A number of T cell-intrinsic peripheral tolerance mechanisms (quiescence, ignorance, anergy, exhaustion, senescence and cell death) restrain autoimmunity and overactive immune responses. Here, the authors provide an integrated perspective of peripheral T cell tolerance by comparing the molecular mechanisms that govern these checkpoints and discussing their role in T cell tolerance and fate regulation.

How does the discovery of SARS-CoV-2 cross-reactive T cells in unexposed individuals change our understanding of the COVID-19 pandemic? In this Perspective, the authors provide a thought experiment to explain why the discovery of cross-reactive T cells may affect disease severity in individuals, but is unlikely to change our estimate of the herd immunity threshold.

Why does the human genome encode more than 300 potential immune inhibitory receptors? Here, the authors propose a categorization of inhibitory receptors — as threshold receptors and negative feedback receptors — that reflects their distinct functions in immune regulation, illustrated using mathematical modelling. This categorization may be useful for the therapeutic targeting of inhibitory receptors.

Recombinant granulocyte–macrophage colony-stimulating factor (GM-CSF) as well as antibodies targeted at GM-CSF or its receptor are being tested in clinical trials for coronavirus disease 2019 (COVID-19). This Perspective introduces the pleiotropic functions of GM-CSF and explores the rationale behind these different approaches.

Why are males more susceptible to severe COVID-19 than females? In this Perspective, Sabra Klein and colleagues consider the sex differences in the immune system that may contribute to this sex bias.

The authors describe how the naive T cell compartment is built across a lifetime. They propose that functional diversity among naive T cells is linked to when they were created. Naive T cells adapt to meet changes in the external environment at different stages of life, persist into adulthood and contribute to the T cell compartment in adults.

As we age, haematopoiesis becomes skewed towards myelopoiesis. Studies of haematopoietic stem cells (HSCs) transplanted into irradiated recipient mice imply that HSC defects are responsible for this ageing effect. Here, the authors urge caution when using irradiated mice to study haematopoiesis ageing, and propose instead that age-related changes in the bone marrow environment and in downstream progenitors, not just HSCs, may also be responsible for myeloid skewing.