Review Articles in 2013

Developing B cells that have successfully expressed a pre-B cell receptor (pre-BCR) undergo clonal expansion, but must exit the cell cycle before rearranging their immunoglobulin light chain loci. The authors discuss how signalling through the interleukin-7 receptor and BCR is coordinated in a mutually exclusive manner to ensure the production of mature B cells without risking leukaemic transformation.

This Review describes the intricate signalling and epigenetic mechanisms that regulate cellular responses to type I interferons. The authors also discuss how persistent interferon-mediated signalling can have detrimental outcomes in autoimmune disease and chronic infections.

Nucleotide oligomerization domain-containing protein 1 (NOD1) and NOD2 are pattern-recognition receptors that detect bacterial peptidoglycan. Signalling through NODs initiates a variety of effector immune responses that seem to be crucial for maintaining immune homeostasis with the host microbiota. Indeed, mutations in NOD1 and NOD2 are associated with both intestinal and extra-intestinal disease. This Review summarizes our current understanding of the NODs.

Most of our understanding of immunological memory comes from studies in mice. However, these studies cannot recapitulate the exposure to numerous diverse pathogens that occurs over decades in humans. But, as reviewed here, recent studies focusing on human memory T cells are revealing important features of these cells, including subset heterogeneity and spatial compartmentalization.

Sepsis is the host inflammatory response to severe, life-threatening infection with the presence of organ dysfunction, and is the most frequent cause of mortality in most intensive care units. Here, the authors argue that, following survival of the initial hyper-inflammatory response, the patient enters a protracted immunosuppressive phase and, therefore, that immunotherapies to treat prolonged sepsis must target the specific cellular dysfunctions associated with immunosuppression.

Prions are infectious proteins that cause fatal neurodegenerative diseases. The prion itself is a misfolded conformer of a normal host protein, which explains why it is difficult for the immune system to respond to it effectively. The authors explain how prions evade, and indeed exploit, immune components to spread to the central nervous system, and they discuss the immunotherapies that are being developed to combat these lethal infections.

Ageing is associated with impaired immune responses to pathogens and vaccines. As described in this Review, ageing results in disrupted regulation of immune cell functions and innate immune receptor signalling, and in the establishment of a persistent pro-inflammatory milieu. The authors explain how this age-associated dysregulation might contribute to chronic inflammatory diseases in the elderly.

Immunology is traditionally viewed as a science of 'mice and men'. However, key insights can come from the study of immune responses in livestock or wild animals. The fact that the most deadly pathogens of humans are often zoonotic in nature lends further weight to the importance of this research. The authors discuss the benefits of, and challenges posed by, these studies.

Semaphorins and their primary receptors, the neuropilins and plexins, participate in a wide range of innate and adaptive immune responses, which has implications for immune disorders such as multiple sclerosis, rheumatoid arthritis and allergy.

The transcription factor T-bet is best known to immunologists as a master regulator of T helper 1 cell differentiation. However, it is becoming apparent that T-bet has important functions in other leukocyte populations, including memory CD8⁺T cells, B cells, innate lymphoid cells, dendritic cells and natural killer cells. This Review discusses these emerging immunological roles for T-bet.

Chemokines control key immunological processes by signalling through G protein-coupled receptors. In addition, chemokines can be bound by atypical chemokine receptors (ACKRs), which are structurally related to conventional chemokine receptors, but which do not mediate classical signalling responses. This Review describes the biological functions of ACKRs and introduces the new nomenclature that has been proposed for this family.

Colonization resistance — protection from exogenous pathogens by commensal bacteria — can be mediated by direct antagonism and by indirect effects on the host immune response. This Review outlines our current knowledge of immune-mediated colonization resistance against clinically relevant, antibiotic-resistant intestinal pathogens and how insights into commensal bacterial species and their mechanisms might be therapeutically used to restore resistance.

It is increasingly understood that autophagy is an ancient defence mechanism that has become incorporated into numerous immunological pathways. As discussed in this Review, its immunological roles include the elimination of microorganisms, the control of inflammation, the regulation of antigen presentation and lymphocyte homeostasis, and the secretion of immune mediators.

Chronic kidney disease affects approximately 10% of the Western population. Recent studies have elucidated some of the immune mechanisms that contribute to kidney injury and disease, which are described in this Review. In addition, the contribution of the kidneys to immune homeostasis and the effects of kidney failure on systemic immune functions are discussed.

In this Review, the authors provide a comprehensive overview of the role of macrophage dynamics in determining the initiation, progression and regression of atherosclerotic inflammation. Understanding the factors that determine the inflammatory state of the plaque may help to identify potential therapeutic targets for plaque regression.

Metalloproteinases are the unsung modifiers of immune responses. Among other activities, they regulate several key signalling pathways, modify the availability of chemokines and influence innate and adaptive immune cell function. As the authors highlight, a lack of these crucial enzymes has dramatic immunological consequences.

This Review summarizes our current understanding of the regulation and function of mitogen-activated protein kinases (MAPKs) in innate immunity, as well as the mechanisms by which pathogens manipulate MAPK activation and the potential of targeting MAPK pathways for the treatment of inflammatory diseases.

This article describes the immunological functions of the scavenger receptors. The authors focus on the structural properties that enable these receptors to respond to a diverse range of both self and non-self ligands. They also discuss the contribution of scavenger receptors to inflammatory diseases.

Intensive research in recent years has highlighted the important and complex roles of microRNAs in the many aspects of T cell biology. In this Review, the authors describe the involvement of microRNAs in the regulatory networks that determine T helper cell fate, function and plasticity, and in the maintenance of immune tolerance.

This Review describes the recent insights that have been made from studying primary immunodeficiency diseases (PIDs). Notably, patients with gene mutations that lead to PIDs often show very different disease phenotypes from those predicted from studies of gene-deficient mice. Thus, these individuals are an invaluable resource for increasing our understanding of human immunology.