Perspectives

Genome editing approaches can be used to confer immune-evasive properties to allogeneic cellular immunotherapies, with the aim of achieving persistent responses and efficiencies that are comparable to those of autologous chimeric antigen receptor T cell therapies. This Perspective discusses how current knowledge about viral or tumour immune evasion could be incorporated into the design of off-the-shelf tumour-specific T and NK cells for the production of cost-effective and scalable cancer immunotherapies.

In this Perspective article, Ley and colleagues explain the association between atherosclerosis and the loss of tolerance to self-proteins. They discuss why re-establishing immune tolerance could improve outcomes for patients with atherosclerotic cardiovascular disease.

In this Perspective, the authors consider the distinct contributions made by T helper 2 cells and group 2 innate lymphoid cells during the course of a helminth infection. Although anti-helminth drugs are effective, reinfection is common and there are currently no available vaccines — a better understanding of T helper 2 cell and group 2 innate lymphoid cell interplay could lead to new anti-helminth strategies.

Epidemiological evidence indicates that physical exercise can lower cancer incidence and mortality. This Perspective discusses the importance of muscular activity for maintaining a healthy immune system and the potential mechanisms by which exercise affects anticancer immunity.

In this Perspective, Honjo and co-workers describe the discovery of PD1 and its journey to become a major target for cancer immunotherapy. It discusses the complex regulatory systems that govern PD1 expression as well as recent insights into PD1 function and the mechanisms of PD1-blocking therapies.

Koohy and co-workers discuss how we must turn to machine-learning approaches to define the antigen specificity of the many millions of possible T cell receptors. They review the models and methods currently being used to predict cognate antigens for orphan T cell receptors.

A disseminated tumour cell will grow only if it arrives at a ‘fertile’ distant site, which as Ana Luísa Correia posits is determined largely by the immune context at the site. Site-specific differences in local immune cell types, ratios and spatial locations influence whether a disseminated tumour cell establishes metastases or is kept dormant.

This Review discusses the evidence for pre-existing cross-reactive immune responses to SARS-CoV-2, which are mainly due to infections with common cold coronaviruses, and how such cross-reactivity affects adaptive immune responses. Furthermore, it explores cross-reactivity in the context of SARS-CoV-2 variants of concern and its implications for vaccine development.

In this Perspective, Francis Carbone considers the unique characteristics of the tissue-resident memory T (T_RM) cell populations that develop in the lungs. He discusses how the different properties of lung T_RM cells may affect immunity to lung infections, including SARS-CoV-2.

In this Perspective, Alain Fischer reflects on the development of gene therapy for patients with inborn errors of immunity. He discusses the challenges the field has faced as well as the progress seen in the past 25 years.

Durham and Shamji review the history and future of allergen immunotherapy for established IgE-mediated hypersensitivity to common allergens. They describe the mechanisms of immunotherapy-induced tolerance and the new strategies being explored to achieve safer, more effective, long-term tolerance.

Many viruses, including SARS-CoV-2, can induce cellular senescence and exacerbate the senescence-associated secretory phenotype, leading to detrimental hyperinflammatory responses. Here, Schmitt and colleagues discuss the role of cellular senescence in COVID-19 as well as progress in the development of therapeutic approaches to eliminate senescent cells.

Here, the authors consider our emerging understanding of COVID-19-associated coagulopathy. They focus on the complex interactions between innate immune, coagulation and fibrinolytic pathways that can lead to potentially life-threatening thrombosis following SARS-CoV-2 infection.

In this Perspective, the authors reflect on the historical development of host-directed immunotherapeutic interventions for viral and bacterial infections, and then focus on how historical insights can be applied to current approaches to therapy of SARS-CoV-2 and Mycobacterium tuberculosis infections.

Mast cells are complex immune cells with varied functions. This Perspective explores the divergent phenotypes and functions of mast cells resulting from both their hard-wired ‘nature’ defined by their ontogeny and the ‘nurture’ they receive within specialized tissue microenvironments.

Improving on current cancer immunotherapies will require engaging immune effectors beyond T cells alone. Predator–prey theory can reveal understudied and counterintuitive facets of antitumour immunity, inspiring new approaches to manipulate the tumour ecosystem in favour of cancer cell extinction.

Understanding of the role of T cells in SARS-CoV-2 infection is of great importance for the design of next-generation vaccines. In this Perspective, Davenport and colleagues discuss the challenges in determining a causal relationship between vaccine-induced T cell immunity and protection from COVID-19.

The cell-autonomous innate immune system has long been considered an evolutionary innovation of metazoans; however, recent evidence challenges this dogma. This Perspective describes the components of antiviral immunity that are conserved from bacteria to humans, and presents potential evolutionary scenarios to explain the observed conservation.

In this Perspective, Amersfoort, Eelen and Carmeliet discuss emerging evidence for tissue- and vessel type-specific immunomodulatory roles of distinct subtypes of endothelial cells, which they collectively refer to as ‘immunomodulatory endothelial cells’ (IMECs).

Individuals with autoimmunity often have an increased frequency of T cells bearing features of follicular helper T cells in their blood. Lucy Walker proposes that alterations in pathways that regulate autoimmunity are coupled to alterations in follicular helper T cell homeostasis.