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Diane Mathis and Christophe Benoist describe how our understanding of the function of autoimmune regulator (AIRE) has developed over the last decade, from its discovery to its role in central tolerance. Key questions that need to be addressed over the next decade are also highlighted.

Mathis and colleagues identify a subset of muscle mesenchymal stromal cells that coordinates tissue immune responses and drives regenerative mechanisms following muscle injury.

Vγ6⁺ Vδ1⁺ γδ T cells control tolerance to cold by activating adipocyte IL-17RC and promoting sympathetic innervation of thermogenic adipose tissue in mice.

Magnetic resonance imaging of magnetic nanoparticles allows monitoring of disease progression in type 1 diabetes. Mathis and colleagues use this approach to predict diabetes onset and identify a pathway important in the regulation of disease progression.

Helper T cell subsets are characterized functionally by the cytokines they produce. Benoist and colleagues demonstrate that in vivo helper T cells do not manifest as discrete helper subsets but rather form a continuum shaped by microbial exposure.

Mathis and colleagues show that the transcriptional regulator Aire preferentially localizes in and activates super-enhancers.

Z-DNA anchors the AIRE-mediated transcriptional program by enhancing the generation of double-stranded breaks and promoter poising.

The lack of generalizability and reproducibility of machine learning models in medical applications is increasingly recognized as a substantial barrier to implementing such approaches in real-world clinical settings. Highlighting this issue, Jie Cao et al. aim to reproduce a recent acute kidney injury prediction model, and find persistent discrepancies in model performance in different subgroups.

An introduction to immunometabolism: the scope and future opportunities in this emerging field.

Both dietary and microbial factors influence the composition of the gut bile acid pool, which in turn modulates the frequencies and functionalities of RORγ-expressing colonic FOXP3⁺ regulatory T cells, contributing to protection from inflammatory colitis.

Visceral adipose tissue contains populations of regulatory T cells that exhibit sexual dimorphism, determined by the surrounding niche, and differ between male and female mice in terms of cell number, phenotype, transcriptional landscape and chromatin accessibility.

FOXP3 deficiency leads to dramatic loss of immune homeostasis. This multicenter collaborative group finds that loss of FOXP3 function only disrupts a few core genes, but this unmasks a degree of systemic inflammation, and it is this environment that then strongly perturbs T_reg cells.

The transcription factor Aire mediates tissue-specific antigen expression in the thymus for T cell central tolerance induction. Here the authors show that Aire, via its CARD ___domain, forms multimers that can misdirect Aire to PML bodies leading to the loss of Aire transcriptional activity and induction of autoimmunity.

During foraging for live prey, zebrafish larvae alternate between persistent exploitation and exploration behavioural states that correlate with distinct patterns of neuronal activation.

Regulatory T (T_reg) cells modulate immune cell responses. Mathis and colleagues review the specialized roles played by tissue-specific Treg cells and reveal new functions that can be attributed to distinct T_reg cell subsets.

What is the role and value of consortium biology in immunology? Here, the participants of the Immunological Genome Project share their thoughts on the benefits and shortcomings of 'big science' and discuss how the immunology community can profit from engaging in this type of discovery-led research.

The Coxsackie B virus has been linked to autoimmune diabetes, and there are two main theories to account for this. The first (molecular mimicry) predicts that pathogen-encoded antigens are similar to self-proteins, priming the immune system to attack self-tissues. The second (bystander activation) holds that the pathogen simply disrupts the equilibrium of self-tolerance, causing self-tissues that would otherwise have been ignored to be attacked. A new study comes down firmly in favour of the bystander-activation theory — for Coxsackie-virus-induced diabetes at least.

Regulatory T (T_reg) cells have distinct transcriptional programs underpinning their suppressive functions. Benoist and colleagues use single-cell RNA-seq to describe the transcriptional landscape of T_reg cells and the effects of T cell–receptor signaling.

Foxp3 is the T_reg cell lineage–defining transcription factor, but its mechanisms of action are still being elucidated. Benoist and colleagues comprehensively generate Foxp3 mutants to delineate how it functions in a cell-context- and molecular-complex-dependent manner.

In these new reports, three different research groups independently find that various T cell populations are crucial mediators of obesity-induced metabolic dysfunction. They also show that pharmacological approaches that target these T cells are beneficial, thus opening the door to possible new therapeutic approaches to treating obesity-related diseases such as diabetes (pages 846–847, 914–920 and 921–929).

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.

How expression of tissue-restricted self antigens is coordinated in medullary thymic epithelial cells has remained unclear. Benoist and colleagues use single-cell RNA sequencing to identify clusters of co-expressed tissue-restricted antigens.

The differentiation of αβ T cells is a complex process. Using data sets from the Immunological Genome Project, Benoist and colleagues identify candidate mediators of key transitions during thymocyte selection and maturation.

Regulatory T cells expressing the transcription factor Foxp3 are known to control autoreactivity during and subsequent to the development of the peripheral immune system. New evidence emphasizes the fact that those cells are constant and powerful guardians against the state of 'horror autotoxicus'.

There are several different types of diabetes, one of which -- insulin-dependent diabetes mellitus -- is characterized by the systematic destruction of insulin-producing β-cells in the pancreatic islets of Langerhans. A new study indicates that the trigger for this self attack may be a superantigen that is produced by a hitherto unknown endogenous retrovirus.

Differentiating neutrophil functional states is difficult. Here the authors show, using single cell RNA-sequencing and trajectory analyses, that mouse neutrophils can be presented as a transcriptome continuum rather than discrete subsets, but are affected by inflammation to express distinct transcriptional states.

The field of immunometabolism (both on the cellular as well as on the organismal level) is advancing rapidly. This article highlights several studies from 2018 that examine how immune cells can regulate systemic metabolism, as well as studies of the impact of organismal metabolism on the immune system in conditions such as obesity and cancer.

The Midwinter Conference of Immunologists is a popular annual fixture for immunologists to discuss the hot topics in immunology while enjoying the mild weather of the West Coast.

Successful microarray experimentation can generate enormous amounts of data, potentially very rich but also very unwieldy. Bold outlooks and new methods for data analysis and presentation should yield additional insight into the complexities of the immune system.