Reviews & Analysis

There is a growing appreciation of how the host inflammatory response is intricately entwined with the various forms of programmed cell death. This Review discusses the signalling mechanisms that link these processes, with a particular focus on how the key mediators of cell death, such as the caspases, are integrated into innate signalling modules.

T helper 17 (T_H17) cells promote protective immune responses against infection, particularly at barrier sites, but they can also have pathogenic roles in inflammatory diseases. In this Review, the authors describe the factors that control the development and maintenance of T_H17 cells, and discuss their diverse functions in both health and disease.

Recent evidence indicates that adaptive T cell-mediated immune responses can regulate innate lymphocytes (natural killer cells and innate lymphoid cells) in an interleukin-2-dependent manner. The authors propose a model in which adaptive T cells function as peripheral antigen-specific sensors that recruit and activate innate lymphocytes to amplify and coordinate local immune responses.

Natural killer T (NKT) cell defects have been implicated in several diseases such as autoimmunity, asthma and cancer, but will targeting them really be of clinical benefit? Here, the authors investigate this question and conclude that more careful studies are needed before the true clinical potential of NKT cell-targeted therapies can be determined.

In this Review, the authors describe how Toll-like receptors (TLRs) assemble with signalling adaptor proteins to form higher-order scaffolds that signal in response to pathogen sensing. Productive TLR signalling involves cooperative assembly, post-translational modification and subcellular localization of the components of the signalling complexes.

The butyrophilins are members of the immunoglobulin superfamily that have previously been poorly understood, however they are now emerging as key modulators of the immune system. Here, the authors describe the diverse ways in which butyrophilins can modify immune cell activity and discuss the potential of targeting this family for therapeutic purposes.

T cell development can be divided into three major regulatory phases by the checkpoints that occur at commitment to the T cell lineage and at β-selection. The three phases are each governed by different gene networks that confer distinct cellular characteristics. The correct developmental programme depends on the sequential operation of these gene networks, and cells that fail to enforce the boundaries between phases may be predisposed to leukaemic transformation.

Cells of the mononuclear phagocyte system (MPS) are usually defined by particular functional or phenotypical characteristics. However, this has led to confusion in the field, as many of the criteria that are used to define a particular cell population may actually be shared with other cell types. In this Opinion article, the authors propose that a new nomenclature that is based on cell ontogeny could enable a more robust classification of MPS cells.

The presence of nucleic acids in the cytosol alerts the cell to viral infection or damaged self. The oligoadenylate synthase (OAS) proteins and cyclic GMP–AMP synthase (cGAS) are enzymes that detect this danger and promote antiviral immunity. Recent structural studies reveal that these enzymes have a common mechanism of action and probably the same evolutionary origin.

T cell subsets have unique metabolic needs. In this Review, the authors explain how metabolic pathways are interconnected with signalling pathways that mediate the activation and differentiation of discrete T cell subsets. They suggest that a better understanding of this complexity will lead to more targeted therapies for immune regulation.

In this Review, the authors discuss how innate immune mechanisms can contribute to the development of neurodegenerative disease. They suggest that both local and systemic inflammation can drive pathological microglial cell activity, thereby leading to neuronal cell dysfunction and disease.

Follicular dendritic cells (FDCs) in lymph nodes support the development of high-affinity antibody responses by retaining antigens at their cell surface for long periods of time. Although FDCs are generally regarded as 'accessory cells' in the germinal centre, recent data suggest that they have more active roles in the development of humoral immune responses. This Review focuses on our current understanding of FDCs.

Inflammation can promote the development of lymphoid structures in tissue sites at which they do not normally occur. Here, the authors discuss how these ectopic lymphoid-like structures arise and, furthermore, how they affect immune responses in the setting of infection and disease.

The technological revolution in vaccination — from the empirical approach pioneered by Jenner and Pasteur to the recent developments in structural and reverse vaccinology, combined with synthetic biology — promises great hope for the development of safer and more effective vaccines against all infectious diseases.

Mast cell granules contain numerous immunomodulatory compounds that are rapidly released in various inflammatory settings. Here, the authors describe the composition, biogenesis and maturation of mast cell granules, and they focus on the biological effects of the mast cell proteases that are released.

In this Review, the authors highlight the importance of the diverse mechanisms that regulate the expression of innate immune genes post transcription. These regulatory mechanisms act at the level of mRNA splicing, mRNA polyadenylation, mRNA stability and protein translation, and they are important for controlling the magnitude and duration of inflammatory responses.

Research into the role of commensal microorganisms in influencing the immune system has mainly focused on bacterial communities. Here, the authors review recent studies that highlight the importance of commensal fungi and how the immune system interacts with these communities at different body sites.

Our understanding of the ontogeny of monocytes and macrophages, as well as their maintenance in the steady state, has recently undergone a renaissance. Here, Ginhoux and Jung discuss the evidence that has changed our view of the relationship between monocytes and tissue macrophages during development and in the steady state.

Recent studies of ontogeny and gene expression have enabled the discrimination of dendritic cell and macrophage subsets in mouse skin and the identification of their human counterparts, which has led to a growing appreciation of the functional specialization of these subsets.

Here, the authors describe the key characteristics of the different antigen-presenting cell (APC) populations that govern T cell development in the thymus. They discuss how the interactions that occur between thymocytes and thymic APCs shape the mature T cell repertoire, and how they subsequently affect the nature of peripheral immune responses.