Perspectives

Neoadjuvant (chemo)immunotherapy has become a new standard-of-care option for patients with cancer. This Perspective discusses the lessons learnt for neoadjuvant immunotherapy in the context of melanoma and where the field is heading next, particularly an increased understanding of the role of immune education in therapy resistance and the need for biomarker-driven therapy personalization to uncouple toxicity from efficacy.

Endometritis can cause infertility and recurrent pregnancy loss and is an important medical and veterinary issue. Here, Nash and Giles provide an overview of the various models that can be used to study uterine inflammation and discuss their value for developing new therapies.

Here, Swirski and colleagues explore how the nervous and immune systems connect and collaborate to respond to internal and external stimuli. In particular, they consider how the exchange of information between both systems is vital for host physiology, in the context of both health and disease.

This Perspective explores how the gut microbiota influences the function and heterogeneity of microglia, highlighting their roles in neurological and neuropsychiatric disorders, and discusses the therapeutic potential, challenges and clinical implications of targeting microbiota–microglia interactions.

In this Perspective, Smyth and Kipnis reappraise the concept of immune privilege in the central nervous system. Although immune privilege was originally thought to involve isolation of the central nervous system from the peripheral immune system, the authors argue that it is instead a special immunological state that involves continuous neuroimmune dialogue.

In this Perspective, Feuerer and colleagues consider how transposable elements (TEs) — which are mobile nucleic acid sequences in the genome — can impact diverse immune responses. For instance, transcription of TEs can activate innate immune pathways that generate type I interferons, TEs can regulate gene expression in immune cells and TEs could potentially be targeted to generate tumour neoantigens for immunotherapy purposes.

Immunoglobulins sample vast swathes of primary sequence and conformational space to generate and select B cell clones with exquisite selectivity and affinity for specific antigens. This Perspective article examines the interplay between antibody diversification mechanisms and highlights the importance of constant regions in influencing the specificity and functionality of individual antibodies.

New immunotherapies have the potential to mediate a sustained remission from certain autoimmune diseases. This has been referred to as achieving an ‘immune reset’ in patients. Here, Junt and colleagues discuss how we can most accurately define the term immune reset and explain the challenges in identifying suitable biomarkers of long-term disease remission.

HIV infection persists under antiretroviral therapy due to a reservoir of latently infected cells. This Perspective discusses how host immune responses might affect the establishment and persistence of the viral reservoir, an understanding of which supports the development of immune-based approaches to ‘cure’ HIV infection by disrupting the reservoir.

The peripheral immune system communicates with the brain through diverse anatomical routes to shape brain physiology. Here we discuss why such diversity is needed and explore how these routes are leveraged during development and hijacked in ageing.

This Perspective discusses current knowledge of the diverse roles played by different macrophage populations within the Mycobacterium tuberculosis-infected lung. The underlying hypothesis is that disease outcome depends on macrophage ontogeny and epigenetic programming, in addition to the immune environment.

There is emerging evidence that mice with a history of microbial exposures can better model the human immune system than laboratory mice maintained in pathogen-free conditions. In this Perspective, Rehermann and colleagues summarize different approaches that have been used to incorporate microbiota and pathogen exposures into laboratory mouse models. They suggest that the term ‘mice with natural microbiota’ should be used instead of ‘dirty mice’ to describe these systems in the future.

The basic-residue-rich sequence (BRS) is a common motif located in the cytoplasmic tail of most immunoreceptors. This Perspective highlights the mechanisms of BRS signalling, its pathophysiological importance and how to harness BRS signalling to develop next-generation immunotherapy.

Thirty years ago, Polly Matzinger introduced the ‘danger theory of immunity’, which proposed that danger and damage have a decisive role in immune responses. In this Perspective, Kroemer et al. reflect on the impact of the danger theory, discuss its molecular foundations and present an extended version of it. They propose that immunological self-tolerance is organized in a hierarchy that functions in a close-to-fail-safe cascade-like fashion, thereby reconciling Matzinger’s danger theory with the self–non-self-discrimination hypothesis.

CAR T cells have transformed the treatment of some haematological cancers. This Perspective explores how insights into T cell receptor signalling have enabled the engineering of CAR formats that can outcompete currently approved CARs in preclinical models and clinical trials.

This Perspective considers present and historical paradigms of therapeutic cancer vaccines and describes a conceptual framework, termed Vax-Innate, to simultaneously generate robust tumour-specific T cell responses and remodel the suppressive tumour microenvironment (TME). The authors detail how this strategy could be achieved through systemic vaccination and by using immune modulators to improve dendritic cell and macrophage function in the TME.

Technological advances in cellular and molecular immunology are providing unprecedented new insights into evolutionary immunology. This Perspective highlights new insights into the immune systems of different vertebrate species and discusses emerging general principles of immune system function.

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.