The assembly of the NLRP3 inflammasome can promote the release of IL-1β/IL-18 and initiate pyroptosis. Accordingly, the dysregulation of NLRP3 inflammasome activation is involved in a variety of human diseases, including gout, diabetes, and Alzheimer’s disease. NLRP3 can sense a variety of structurally unrelated pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) to trigger inflammation, but the unifying mechanism of NLRP3 activation is still poorly understood.
T cells are a central component of defenses against pathogens and tumors. Their effector functions are sustained by specific metabolic changes that occur upon activation, and these have been the focus of renewed interest. Energy production inevitably generates unwanted products, namely reactive oxygen species (ROS), which have long been known to trigger cell death. However, there is now evidence that ROS also act as intracellular signaling molecules both in steady-state and upon antigen recognition.
ILC2s are critically involved in allergic responses, but the mechanisms by which they are regulated remain unclear. Li et al. demonstrate that the VHL-HIF axis is essential for ILC2 maturation and function via inhibition of glycolysis and induction of IL-33 receptor expression. These findings have implications for identifying therapeutic targets for allergic diseases.
Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR
Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR, Published online: 12 February 2018; doi:10.1038/s41590-018-0051-0
Regulatory T (Treg) cells have distinct transcriptional programs underpinning their suppressive functions. Benoist and colleagues use single-cell RNA-seq to describe the transcriptional landscape of Treg cells and the effects of T cell–receptor signaling.
Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes
Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes, Published online: 12 February 2018; doi:10.1038/s41590-018-0046-x
Wang and colleagues show that the transcription factor Hoxb5, which is expressed in uncommitted hematopoietic progenitor cells but is absent from committed B cells and T cells, can reprogram pro-pre-B cells into functional early T cell lineage progenitors.
Along with the maintenance of symbiotic mutualism with commensal microbes and protection against invasive infections common to all mucosal barrier tissues, female reproductive tissues have additional, unique tasks that include dynamic cyclic cellular turnover in menstruation and immunological tolerance to genetically foreign fetal antigens in pregnancy. Here we review current knowledge on distinct features of the immune cells in female reproductive tissue with regard to antimicrobial host defense and adaptations to accommodate the fetus during pregnancy.
Despite some major progress made in developing tuberculosis (TB) vaccine strategies, with a dozen novel vaccines currently in the clinical pipeline, the world is still missing an effective TB vaccine. This questions whether any major breakthroughs can be achieved without making a drastic departure from the current strategy, which creates a state of ‘near-natural immunity’, imitating the natural immunity developed after Mycobacterium tuberculosis (Mtb) infection. Here, we argue instead that mounting evidence suggests an effective strategy ought to induce a state of all-around ‘un-natural’ immunity comprising trained innate immunity (TII), tissue-resident memory T cells (TRM), and anti-Mtb surface antibodies in the lung.
It has been challenging to map leukocytes in the brain, particularly during pathology. Mrdjen et al. combine high-dimensional single-cell cytometry with fate mapping to capture the immune landscape of the brain. They identify different subsets of myeloid cells and the phenotypic changes in CNS immune cells during aging and in models of Alzheimer’s disease and multiple sclerosis.
γδ T cell frequency increases late during mouse and human malaria. Mamedov et al. show that oligoclonal TRAV15N-1 (Vδ6.3) γδ T cells expand across various tissues and prevent late-stage parasitemic recurrence. These protective γδ T cells exhibit a distinct transcriptional profile that includes abundantly expressed M-CSF, which protects against Plasmodium recurrence.
Metabolic exhaustion in infection, cancer and autoimmunity
Metabolic exhaustion in infection, cancer and autoimmunity, Published online: 05 February 2018; doi:10.1038/s41590-018-0045-y
McKinney and Smith review the metabolic exhaustion of T cells in infection, cancer and autoimmunity
I am, and have always been, mainly driven by my curiosity of trying to understand how nature works. In my case, academia does not ‘run in the family’. My younger brother is now a postdoc, but at the time I was starting out, I didn’t have anybody in the family to inspire me for such a career. I didn’t even know that ‘academic scientist’ was a job when I started university. It really ‘just happened’ and somehow was the logical consequence of the things I found interesting.
The functional capacities of natural killer (NK) cells differ within and between individuals, reflecting considerable genetic variation. ‘Licensing/arming’, ‘disarming’, and ‘tuning’ are models that have been proposed to explain how interactions between MHC class I molecules and their cognate inhibitory receptors – Ly49 in mice and KIR in humans – ‘educate’ NK cells for variable reactivity and sensitivity to inhibition. In this review we discuss recent progress toward understanding the genetic, epigenetic, and molecular features that titrate NK effector function and inhibition, and the impact of variable NK cell education on human health and disease.
Luo et al. show that CD40 and BCR signaling in GC B cells is rewired to control very different pathways, and both signals are required for optimal induction of c-Myc, suggesting a mechanism of signaling-directed positive selection of GC B cells.
Glucocorticoids have strong immunosuppressive effects, yet their physiological functions in the immune system remain unclear. Shimba et al. demonstrate that glucocorticoids drive IL-7R expression in a diurnal fashion, which induces the redistribution of T cells between peripheral blood and lymphoid organs via CXCR4 expression and enhances adaptive immune responses.
In comparison with the major histocompatibility complexes (MHCs) of typical mammals, the chicken MHC is simple and compact with a single dominantly expressed class I molecule that can determine the immune response. In addition to providing useful information for the poultry industry and allowing insights into the evolution of the adaptive immune system, the simplicity of the chicken MHC has allowed the discovery of phenomena that are more difficult to discern in the more complicated mammalian systems.
The immunology of hepatocellular carcinoma
The immunology of hepatocellular carcinoma, Published online: 29 January 2018; doi:10.1038/s41590-018-0044-z
Primary liver cancer, of which hepatocellular carcinoma is the most common form, is the second leading cause of cancer-related death. Heikenwalder and colleagues review the important inflammatory component underlying hepatocellular carcinoma and consider potential directions for therapy.
The mechanisms by which IL-10 facilitates the establishment of chronic infections are not fully understood. Smith et al. demonstrate that during chronic infections, IL-10 upregulates N-glycan branching on CD8+ T cell surface glycoproteins, which reduces signal transduction downstream of the T cell receptor and decreases CD8+ T cell antigen sensitivity and capacity to control pathogen burden.
An increased understanding of infant antibody responses to RSV infection would greatly facilitate vaccine development. Goodwin et al. isolate and structurally characterize antibodies from RSV-infected infants and identify potent neutralizing antibodies that lack somatic hypermutation. The results provide a framework for the rational design of age-specific RSV vaccines.
CD8 T cells are crucial for long-term immunity. Nevertheless, the in vivo differentiation of human naïve CD8 T cells into effector and memory populations remains ill-defined. A recent study assesses the in vivo turnover of human antigen-specific CD8 T cells and suggests that long-lived memory cells arise from effector cells.