Perspectives in 2024

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.