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The cytokine TGF-β maintains the residency of cells of the immune system in barrier tissues. Kaplan and colleagues demonstrate that specific integrins expressed by epithelial cells activate latent TGF-β and that this is critical to maintain residency of cells of the immune system in the skin and gut.
Immature self-reactive B cells undergo central tolerance as they emerge from the bone marrow. Xiao and colleagues show that B cell tolerance requires downregulation of the microRNA miR-148a, as aberrant expression of miR-148a increases survival of autoreactive B cells and contributes to autoimmunity.
Van Heijst and colleagues show that CD4+ T cells are programmed to downregulate TCR expression at the peak of clonal expansion in proportion to the strength of initial antigen recognition.
Activation of NK cells by hematopoietic targets is controlled by the SLAM receptors and SAP adaptors. Veillette and colleagues show that SLAM-SAP pathways also control NK cell cytotoxicity against nonhematopoietic targets through SLAMF6 homotypic interactions and education.
Epithelia continually undergo apoptosis, but the physiological importance of this is unclear. Shibuya and colleagues show that apoptotic epithelial cells bind the glycoprotein CD300a on a dendritic cell subset at barrier surfaces and this negatively regulates commensal-driven Treg cell proliferation.
SHARPIN is a component of the linear-ubiquitin-chain–assembly complex that positively regulates activation of the transcription factor NF-κB. Liu and colleagues show that SHARPIN regulates TCR signaling independently of NF-κB and that its deficiency impairs Treg cell generation.
cGAS is an important sensor of cytosolic DNA, but the mechanisms that regulate it remain largely unknown. Fan and colleagues demonstrate that cGAS and its DNA-binding activities are negatively regulated by glutamylation.
T cell anergy is a well-established phenomenon, but its physiological role is unclear. Mueller and colleagues demonstrate that anergic self-reactive T cells are present at steady state and that these are predisposed to generate peripheral regulatory T cells.
Regulatory T (Treg) cells have a distinct cellular metabolism compared to effector T cells. Chi and colleagues show that autophagy is required to maintain the functional integrity and metabolic homeostasis of Treg cells in the face of inflammatory environmental cues.
Sun and colleagues show that the deubiquitinase Trabid mediates the TLR-induced deubiqutination and stabilization of the histone demethylase Jmjd2d at the Il12 and Il23 promoters in dendritic cells.
The precise lineage relationship between innate lymphoid cells and lymphoid tissue–inducer cells is poorly understood. Using single-cell transcriptional analysis and cultures of fetal liver precursor cells, Bendelac and colleagues define the divergence of these cells.
The transcription factor Blimp-1 is required for the differentiation of activated B cells into plasmablasts. Nutt and colleagues show that plasma cells need Blimp-1 to maintain antibody production by regulating the kinase mTOR and unfolded-protein-response pathways.
Blimp-1 is known to act as a transcriptional repressor by suppressing genes associated with mature and activated germinal center B cells. Busslinger and colleagues show that Blimp-1 can also directly activate gene expression in plasma cells, including those encoding proteins that regulate the production of membrane-bound immunoglobulin versus secreted immunoglobulin.
Inflammation can boost antigen-specific adaptive immune responses. Ziegler and colleagues show that type I interferon-mediated inflammation can also affect bystander naive CD4+ T cells by transiently increasing their expression of Foxp3, which might limit aggressive responses against self-antigens.
CD4+ T cell tolerance can be enforced by various mechanisms. Jenkins and colleagues use mice with entirely intact polyclonal T cell repertoires to comprehensively define the mechanisms of self-tolerance.