Reviews & Analysis

Recent studies have revealed a specialized population of ‘exhausted’ CD8⁺ T cells that expands on immune checkpoint blockade therapy for cancer and may explain how T cell responses are maintained in chronic conditions. Here, the authors describe their phenotypic, developmental and functional characteristics and why they should be harnessed for successful immunotherapy.

In this Viewpoint article, Nature Reviews Immunology invites 18 experts to discuss the nature of T cell exhaustion. How should T cell exhaustion be defined and what are the developmental relationships between exhausted T cell subsets? The contributors share their thoughts on key recent developments in the field.

Understanding why some patients and not others respond to immune checkpoint blockade for cancer is crucial for extending benefit from this therapy. Here the authors describe how tumour cells can resist immune checkpoint blockade, for example, by resistance to interferon signalling and through immune-evasive oncogenic signalling pathways.

Host-derived molecules, the so-called damage-associated molecular patterns (DAMPs), can induce sterile inflammation. This Review provides an overview of DAMP-sensing receptors, discusses the crosstalk between these receptors and explores their role in disease.

The authors consider the inflammatory basis of type 1 and type 2 diabetes. In particular, they focus on the role of IL-1β in both diseases and discuss the feasibility of targeting innate immune mechanisms in the clinic.

There is growing interest in harnessing dendritic cells for cancer immunotherapy. Here the authors describe the roles of dendritic cells in the tumour microenvironment and the different strategies that are being developed to target these cells in the clinic.

Recent advances in single-cell antibody cloning technologies have enabled the molecular characterization of monoclonal antibodies against Plasmodium falciparum parasites, which has significantly enhanced our understanding of how these antibodies are generated, as well as their epitope specificity and binding modes.

Universal cells — here defined as cells that are invisible to the immune system — could potentially have many uses in transplantation medicine. This Review discusses how far we have come in creating such cells and the lessons that nature can teach us about immune evasion.

Platelets are best known for their roles in haemostasis, but they also contribute to host immunity. In this Review, Gaertner and Massberg consider how platelets ‘patrol the vascular highway’ to shape immune responses during infection and cancer.

Emerging studies highlight cell metabolism as a crucial regulator of T cell quiescence and activation. This Review describes how immunological cues and nutrients fine-tune metabolic programmes and signalling networks that together promote T cell quiescence exit.

Here, the authors describe how metabolic disorders, such as type 2 diabetes and nonalcoholic fatty liver disease, are driven by alterations in the composition of the intestinal microbiota and its metabolites, which translocate from the gut across a disrupted intestinal barrier and contribute to metabolic inflammation.

The identification of suitable tumour-specific antigens, which can be targeted by vaccine-based or T cell-based immunotherapies, is challenging. This Review explores the potential of alternative splicing to generate unique tumour antigens and discusses methods for their identification.

This Review focuses on evidence implicating innate lymphoid cells (ILCs) as previously unappreciated regulators of the adaptive immune system. Reciprocal interactions between ILCs and adaptive immune cells are a crucial determinant of tissue immune responses during homeostasis and disease.

Mucosal-associated invariant T cells display innate, effector-like qualities and are involved, in various ways, in infectious and non-infectious diseases. Insights into their activation, tissue migration and function are revealing their beneficial and deleterious roles in disease.

Sleep enhances immune defences, and afferent signals from immune cells promote sleep. However, in response to chronic stressors, the normally adaptive function of sleep can become dysregulated, with implications for inflammatory and antiviral responses.

Ultraviolet radiation (UVR) modulates innate and adaptive immune responses at both local and systemic levels; understanding the mechanisms of this immunomodulatory capacity can explain how UVR has both beneficial and detrimental effects.

New findings indicate that IFN-λ (type III IFN) has a non-redundant role in antiviral, antifungal and antiprotozoal defences of mucosal barriers that differs in several aspects from the functions of IFN-α and IFN-β (type I IFNs).

It is well known that immune cells can have profound effects on bone cells, but this interaction is not unidirectional. In this review, Tsukasaki and Takayanagi explore the reciprocal dialogue between bone cells and immune cells during health and disease.

This Review describes how the body attempts to maintain a functional T cell compartment with advancing age. It explores whether T cell ageing reflects cellular senescence or the failure to maintain quiescence and instead undergo differentiation.

Exercise is known to have beneficial effects on the immune system. In this Review, Janet Lord and colleagues discuss the evidence that exercise can prevent diseases associated with ageing by protecting against immunosenescence.