Reviews & Analysis

In this Review, Rolls and colleagues discuss regulation of immune responses by the nervous system. The authors focus on the benefits of neuronal regulation of immunity, the mechanisms involved and the brain areas involved in neuro-immune crosstalk.

This Review covers our current understanding of the roles of IL-9-producing T cells in allergy and cancer. Should these cells be classified as a distinct IL-9-producing T helper cell subset? And can we therapeutically target them for the treatment of chronic allergic diseases and cancer?

Antibody-dependent enhancement (ADE) has been described as a mechanism that contributes to the pathogenesis of dengue virus infection. Limited evidence also suggests that it can also occur in other viral infections. Here, the authors explore the history of the ADE phenomenon, discuss the diversity of Fc effector functions and consider its potential relevance in the context of SARS-CoV-2 infection.

Constitutive innate immune mechanisms, such as restriction factors, RNA interference, antimicrobial peptides, basal autophagy and proteasomal degradation, exert early host defence activities that also aim to minimize tissue damage and homeostatic disruption by limiting the activation of inducible innate immunity.

Immunometabolism has a key role in HIV-1 pathogenesis, with the metabolic state of T cells and macrophages determining their susceptibility to infection, the metabolism of immune cells shaping their response to infection and metabolic products driving inflammation during infection.

In this Progress article, Wang and Colonna highlight a flurry of recent reports that have shaped our understanding of how environmental cues and clock genes regulate group 3 innate lymphoid cells. They consider the implications of these findings for intestinal immunity.

The ATP–adenosine pathway plays an important role in modulating innate and adaptive immune responses in the tumour microenvironment. Here, the authors focus on CD39, a key enzyme in the ATP–adenosine pathway, and examine immunotherapeutic strategies that target it.

In this Progress article, Zeyu Chen and E. John Wherry summarize early reports of the T cell responses observed in patients with COVID-19, emphasizing how different immune response characteristics in different patients may reflect a spectrum of disease phenotypes.

In this Viewpoint, six leading experts consider the ways in which the microbiota can influence immune responses to cancer. Immunotherapies have been revolutionary in the treatment of cancer, but will we one day further increase their efficacy with microbiota-derived drugs?

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.

The authors compare the thymic development of several innate-like T cell populations, including natural killer T cells, mucosal-associated invariant T cells and γδ T cells. They focus on the cytokines, surface molecules and transcription factors that are necessary for the development of these cells and highlight some of the key differences from conventional T cell development.

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.

In this Viewpoint article, members of the Optimmunize consortium discuss the evidence for non-specific and sex-differential effects of vaccines and how this information might inform vaccine design and policy, including in relation to the COVID-19 pandemic.

T cells play a central role in immune responses to cancer. In this guide to cancer immunotherapy, the authors provide a comprehensive historical and biological perspective on cancer immunotherapy, with a focus on current and emerging therapeutic approaches that harness T cells to fight cancer.

Clonal expansion is no longer only the preserve of adaptive lymphocytes. Innate lymphocytes, in particular natural killer cells, also undergo clonal expansion in response to infection. Here, the authors compare and contrast this process for adaptive and innate lymphocytes.

This Progress article from Merad and Martin examines our current understanding of the excessive inflammatory responses seen in patients with severe COVID-19. The authors focus on the emerging pathological roles of monocytes and macrophages and discuss the inflammatory pathways that are currently being targeted in the clinic.

This Review from Gause, Rothlin and Loke considers how different layers of complexity influence the development of type 2 immunity. In particular, the discussion focuses on how variations in the initiating stimuli, tissue microenvironments and host genetics can lead to heterogeneity in type 2 immune responses.

The clinical activity of cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitors has largely been attributed to their capacity to block the proliferation of tumour cells, but increasing evidence discussed in this Review suggests that these inhibitors also have immunomodulatory effects that promote antitumour immune responses.