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Like walking on a tightrope, immune responses balance the eradication of pathogens and collateral damage to the host. This month's Focus features a series of specially commissioned articles that discuss the cellular and molecular mechanisms that regulate this fine balance (http://www.nature.com/ni/focus/checksandbalances/). Artwork by Lewis Long.
The axis of lymphotoxin and its receptor LTβR influences the composition of the host gut microbiome, leading to excessive weight gain in hosts fed a high-fat diet.
The secretion of cytokines by helper T cells is affected by the cytokine environment and by costimulatory signals. Engagement of the receptor OX40 on T cells increases expression of the transcription factor TRAF6, activates the alternative transcription factor NF-κB pathway and induces the production of interleukin 9.
Foxp3 protein complexes orchestrate the transcriptional network of regulatory T cells. The Foxp3 interactome is now identified and may act as a genetic switch that controls the differentiation of regulatory T cells.
Innate immune responses influence the composition of gut microbiota. Fu and colleagues show that weight gain incurred with high-fat diets is dependent on intact lymphotoxin signaling that regulates IL-23 and IL-22 production.
The role of type I interferon in bacterial infection is poorly understood. Sad and colleagues demonstrate that Salmonella-triggered production of type I interferon induces macrophage necroptosis, evasion of the immune response and dissemination of bacteria.
'Lymphoid priming' in human bone marrow is traditionally thought to begin with the expression of CD10 on CD34+ progenitors. Crooks and colleagues now demonstrate lymphoid priming in a subset of CD10–CD34+ progenitors that are CD62Lhi.
Transcription factor Foxp3 is essential for the development and function of regulatory T cells, but it does not act in isolation. Benoist and colleagues identify a quintet of factors that facilitate transcriptional regulation by Foxp3.
TH9 cells secrete copious amounts of IL-9, but how their generation is controlled remains poorly defined. Li and colleagues demonstrate that ligation of the costimulatory receptor OX40 potently generates TH9 cells in a manner dependent on noncanonical NF-κB signaling.
Exposure to interleukin 23 (IL-23) is required for the induction of pathogenic TH17 cells. Kuchroo and colleagues show that IL-23-dependent induction of the cytokine TGF-β3 produces a molecular signature characteristic of highly pathogenic TH17 cells.
Lanier and colleagues systematically define the transcriptome of mouse natural killer cells in several contexts, including activation states and relative to all other lymphocyte and myeloid populations profiled by the Immunological Genome Project consortium.
The transcription factor Foxp3 is essential for the function of regulatory T cells. Rudensky and colleagues show Foxp3 participates in large protein complexes that regulate gene expression of many of these components in self-reinforcing networks.
Five specially commissioned reviews and commentaries discuss the metabolic requirements of immune responses and the regulatory circuits that balance eradication of the pathogen with minimal collateral damage to the host.