ON THE COVER
Zhang et al. describe the events that collectively account for the “macrophage disappearance reaction” in the peritoneal cavity. The cover shows a confocal image of whole-mount preparation staining of the aggregates for fibrin(ogen) and macrophage markers. See page 1291.
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IL2RB maintains immune harmony
Autosomal recessive mutations in IL2RB shape immunity and peripheral immune tolerance.
Modulating inflammation for cancer therapy
This review provides a concise overview of pro- and anti-inflammatory approaches in current tumor therapy.
Development of immune checkpoint therapy for cancer
Fritz and Lenardo discuss the basic science and clinical discoveries of immune checkpoint blockade, which boosts antitumor immunity and increases survival of patients with cancer.
Brief Definitive Reports
A novel human IL2RB mutation results in T and NK cell–driven immune dysregulation
A novel homozygous mutation in human IL2RB results in decreased IL-2Rβ protein expression and dysregulated IL-2/15 signaling. This hypomorphic mutation leads to decreased regulatory T cell frequency and an abnormal NK cell compartment, with clinical manifestations of autoimmunity and susceptibility to CMV.
The Notch signaling pathway promotes basophil responses during helminth-induced type 2 inflammation
Basophils promote type 2 inflammation that mediates worm clearance during murine infection with the gastrointestinal helminth parasite Trichuris muris. Webb et al. show for the first time that basophil–intrinsic Notch signaling is required for basophil gene expression and a functional program that support helminth expulsion.
Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria
Plasmodium falciparum–infected individuals in a malaria-endemic region have an abundance of adaptive NK cells that correlates with resistance to malaria. Adaptive NK cells dominate antibody-dependent responses to P. falciparum–infected red blood cells and may contribute to acquired immunity to malaria.
Expression of factor V by resident macrophages boosts host defense in the peritoneal cavity
Clotting factors made by resident peritoneal macrophages promote microbial trapping in fluid microenvironments where microbes might otherwise escape.
Technical Advances and Resources
HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells
B cells edited by CRISPR/Cas9 to express anti–HIV-1 antibodies participate in humoral immune reactions after immunization and secrete neutralizing serum titers of anti-HIV antibodies in vivo.
Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance
Zhang et al. identify human IL-2Rβ deficiency as a cause of severe immune dysregulation. The hypomorphic gene mutations reveal variable IL-2Rβ expression and function between different lymphocyte subsets as a means of selectively modulating immune responses.
T cell anergy in perinatal mice is promoted by T reg cells and prevented by IL-33
Perinatal T cells broadly access nonlymphoid tissues, where they are exposed to sessile tissue antigens. Here, Tuncel et al. demonstrate that the availability of Foxp3+ regulatory T cells and IL-33 determine the outcome of such encounters.
Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer
Tiwari et al. identify metabolically activated macrophages in obese mammary adipose tissue as an important source of IL-6, which fuels triple-negative breast cancer stemness and tumorigenesis through GP130 signaling. These mechanistic insights provide potential targets for treating obesity-associated triple-negative breast cancer.
Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity
Medina et al. demonstrate that Kit oncogene activity in gastrointestinal stromal tumor modulates the CD103+CD11b− dendritic cell (DC) lineage. The antitumor efficacy of oncogene inhibition initially depends on preexisting immunity orchestrated by CD103+CD11b− DCs, but subsequently is limited by a decrease in DC lineage maturation.
Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET
Jia et al. demonstrate that lamin B1 acts as a tumor suppressor in lung cancer. Lamin B1 loss promotes lung cancer development and metastasis by loss of PRC2 recruitment to chromatin and activation of the RET/p38 signaling axis.
Hes1 attenuates type I IFN responses via VEGF-C and WDFY1
Transcription factor Hes1 acts as a homeostatic negative regulator of type I interferon production to restrain interferon-mediated immune responses, including antiviral immunity and autoimmune conditions. Mechanistically, Hes1 suppresses interferon expression by targeting a regulatory circuit composed of WDFY1 and VEGF-C.
Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia
Fyn kinase mediates aggregated α-synuclein (αSyn) uptake as well as αSyn-mediated proinflammatory signaling in microglia, leading to NLRP3 inflammasome activation and neuroinflammation in Parkinson’s disease.
Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response
The endoribonuclease Regnase-1 suppresses inflammation through RNA degradation. Here, we show that Regnase-1 is phosphorylated and inactivated by the Act1-TBK1-IKKi axis during IL-17 stimulation. Moreover, this phosphorylation substantially contributes to the mRNA stabilization needed for amplification of TH17-cell–mediated inflammation.
BCL6 corepressor contributes to Th17 cell formation by inhibiting Th17 fate suppressors
Th17 cells provide a protective immunity against extracellular bacterial and fungal pathogens. Kotov et al. identify and characterize a mechanism by which BCOR promotes Th17 formation after Streptococcus pyogenes infection by repressing genes that inhibit the Th17 lineage.
Correction: A novel human IL2RB mutation results in T and NK cell–driven immune dysregulation