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Immature B cells expressing self-reactive BCRs induce anergy programs to promote tolerance. Busslinger and colleagues show that the transcription factor Ikaros enforces anergy by inducing transcription of negative-feedback regulators of the BCR and TLR–MyD88 pathways.
Marichal and colleagues show that lung neutrophils in mice exposed to three distinct pro-allergic conditions release neutrophil extracellular traps that potentiate allergen uptake by dendritic cells and type 2 allergic inflammation.
Cantrell and colleagues perform a comparative quantitative mass spectrometric analysis of the proteomes of naïve and activated CD4+ and CD8+ T cells. Proteomes are dynamically regulated and mTORC1 inhibition leads to differential consequences depending on cell state.
Gaudenzio and colleagues show that house dust mite extracts directly activate TRPV1+ sensory neurons, which promote allergic skin inflammation by inducing the degranulation of mast cells through the release of the neuropeptide substance P and activation of MRGPRB2.
Tissue-resident memory T cells (TRM cells) are important for the localized protection of specific body compartments. Nakayama and colleagues identify heterogeneity in lung TRM cells, with one subset driving fibrosis and inflammation and another reining in pathology in response to fungal challenge.
Malissen and colleagues provide a quantitative systems-level analysis of 15 distinct signalosomes that form within minutes of TCR stimulation of primary CD4+ T cells.
A20, encoded by TNFAIP3, is a negative-feedback inhibitor of NF-κB. Grey and colleagues identify natural human variants of TNFAIP3, which lower A20 activity and increase autoinflammatory responses. These alleles were inherited by descendants of Denisovans who crossed the Wallace Line to inhabit Oceania.
Hess and colleagues perform metabolic screens in B cells from patients with primary antibody deficiency and find that germline mutations in the succinate dehydrogenase subunit SDHA drive the expression of the cytokine IL-6 in patients with persistent polyclonal B cell lymphocytosis.
Exhaustion is an acquired state of T cell dysfunction. Sharpe and colleagues demonstrate that the phosphatase PTPN2 supports a T cell-intrinsic exhaustion program in both chronic infection and cancer models.
The precise role of follicular regulatory (TFR) cells in the control of the germinal center (GC) reaction is unclear. Sage and colleagues develop a TFR cell-deleter mouse that allows specific temporal deletion and show that TFR cells primarily control early but not late GC responses.
Screaton and colleagues describe a protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection.
Pre-B cells undergo a transition checkpoint needed for developmental progression. Mandal and colleagues show that the CXCL12–CXCR4 signaling axis orchestrates late B cell lymphopoiesis by suppressing Myc and cyclin D genes and promoting Rag-mediated recombination of immunoglobulin light-chain genes.
Love and colleagues show that β-selection-associated proliferation requires the combined activity of SCF ubiquitin ligases that contain the F-box proteins Fbxl1 and Fbxl12, which are induced by Notch and pre-TCR signals, respectively.
Protein transcription factor paralogs are not equivalent and serve distinct roles in immune cells. Merkenschlager and colleagues show that RUNX1 and RUNX3 differ in binding strength to motif sequences and how this leads to differential functional activities.
MAIT cells recognize the microbial metabolite 5-OP-RU and are selected on DP thymocytes expressing the MHC class Ib molecule MR1. Lantz and colleagues identify 5-OP-RU-specific thymocytes that are selected on thymic epithelial cells and differentiate into naive T cells.
Multiple cytokines in the proinflammatory IL-1 family share the co-receptor IL-1R3. Dinarello and colleagues show that a fully humanized antibody to IL-1R3 can effectively control inflammation and disease mediated not only by IL-1 but also by IL-33 and IL-36.
Beutler and colleagues identify skywarp (swp) mice, which exhibit a hypomorphic variant of the U5 splicing protein SNRNP40 and aberrant mRNA splicing specifically in lymphocytes and hematopoietic stem and progenitor cells, suggesting alternative splicing influencing immune cell function.
Classical type 1 dendritic cells (cDC1s) are essential for activation of antiviral and anticancer T cell responses. Murphy and colleagues describe a genetic circuit that involves the transcription factors Nfil3, Id2 and Zeb2. This circuit imposes a molecular switch that allows cDC1 specification and development.
PlGF is an important vascular endothelial growth factor which has not been widely implicated in immune function. Kim and colleagues demonstrate that PlGF is selectively secreted by TH17 cells to promote angiogenesis but in turn also strongly supports TH17 cell differentiation yet inhibits regulatory T cell function.
The transcription factor IRF8 is essential for classical type 1 dendritic cell (cDC1) development. Murphy and colleagues investigate in detail the molecular control of cDC1 fate specification by systematically unpicking the IRF8 enhancer regions.