Issues

Cildir et al. discuss the recent findings in transcriptional regulation of mast cell development and activation and provide insights into the plasticity and clinical targeting of mast cell functions.

ILC2s interact with CD4 T cells during immune responses against parasitic helminths. Schwartz et al. describe that PD-L1–expressing pulmonary ILC2s stimulate CD4 T cells via PD-1 to up-regulate the type 2 master transcription factor GATA3 and thereby promote IL-13 production from Th2 cells.

Zhang et al. show that hyperphosphorylated STAT1 in patients with STAT1 gain-of-function and STAT3 loss-of-function is caused by impaired SOCS3 expression and leads to upregulation of PD-L1 and defects in Th17 cell differentiation that underlie susceptibility to chronic mucocutaneous candidiasis in these patients.

Luo et al. demonstrate that annexin A2 is required to maintain vascular integrity in the hypoxic mouse lung. A2 prevents extravasation of fluid and leukocytes by promoting activity of the phosphatases VE-PTP and SHP2, thereby modulating phosphorylation of vascular endothelial cadherin.

Schwerd et al. report a novel homozygous missense substitution in the cytokine co-receptor GP130 encoded by IL6ST. This is associated with defective IL-6, IL-11, OSM, and IL-27 signaling and causes immunodeficiency and skeletal abnormalities with similarities to STAT3 hyper-IgE syndrome.

Immune responses that develop in survivors of filovirus infection may indicate critical parameters that could inform rational vaccine development. Stonier et al. characterize immune responses in Marburg virus survivors and demonstrate robust CD4⁺ T cell responses but limited CD8⁺ T cell and neutralizing antibody responses.

Induction of broadly neutralizing antibodies (bNAbs) to HIV would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing bNAb precursors. Medina-Ramírez et al. developed a BG505 SOSIP.v4.1-GT1 trimer that activates bNAb precursors in vitro and in vivo.

In this article, Mukherjee et al. show that the pathologic and clinical alterations of type 2 diabetes can be induced in vitro and in vivo by prion-like transmission of IAPP misfolded aggregates, supporting an important role for IAPP aggregation in the disease.

It is unclear how progranulin deficiency causes frontotemporal dementia, a neurodegenerative disease characterized by TDP-43 inclusions. Chang et al. show that loss of progranulin causes impairment of autophagy and autophagy signaling, which leads to accumulation of pathological TDP-43 in neurons.

Karmaus et al. show that loss of mechanistic target of rapamycin complex 1 (mTORC1) signaling impairs myelopoiesis. M-CSF–dependent myelopoiesis requires mTORC1 signaling and anabolic metabolism, which in turn promote expression of M-CSFR and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis.

High-molecular-weight kininogen (HK) is a plasma protein. Yang et al. show that HK binds LPS and supports endotoxemia. Blockade of their binding attenuates circulating LPS level. Therefore, HK is essential for endotoxemia and is a new target for LPS clearance and sepsis treatment.

Zhang et al. show that Golgi-mediated protein kinase D (PKD) signaling is required and sufficient for NLRP3 inflammasome activation. PKD at the Golgi phosphorylates NLRP3 to release it from mitochondria-associated endoplasmic reticulum membranes, allowing for assembly of the mature inflammasome in the cytosol.

Metastasis is the primary cause of cancer death. Weichand et al. describe a new mechanism explaining how tumor-associated macrophages contribute to metastatic spread, which involves promoting tumor lymphangiogenesis via S1P receptor 1 and the NLRP3 inflammasome.

CD55 is a membrane complement regulatory protein that attenuates complement-mediated cytotoxicity. Saygin et al. elucidate a new role for CD55 as a signaling hub for cancer stem cell self-renewal and cisplatin resistance pathways in endometrioid tumors and open a new line of research into chemotherapeutic-refractory cancers.

During early thymocyte development, coordinated JAK/STAT5 and SFK/pre-TCR signaling is critical for T cell lineage commitment and αβ versus γδ specification. Wiede et al. show a role for the tyrosine phosphatase PTPN2 in attenuating SRC family kinase LCK and STAT5 signaling to regulate αβ and γδ T cell development.

Wang et al. show cooperation between MYD88^L265P and CD79B mutations dysregulating B cell responses to self-antigen and differentiation into plasma cells. Their results reveal that CD79B and surface IgM constitute a rate-limiting checkpoint against MYD88^L265P, explaining the co-occurrence of MYD88 and CD79B mutations in human lymphomas.

The transcriptional regulator of B cell differentiation, Blimp-1, regulates antibody production by plasma cells after antigen stimulation. Savage et al. demonstrate that spontaneous “natural” IgM and IgG3 production is provided by a heterogeneous set of B-1–derived plasma cells and by B-1 cells; the latter neither express nor require Blimp-1 for maximal antibody production.

Watanabe et al. report that, contrary to the prevailing paradigm, there are unique cellular requirements for B7 and CD40 expression in primary GC responses. B7 is required on DCs but not on B cells, whereas CD40 is required on B cells but not on DCs for generation of Tfh cells, GC B cells, and high-affinity class-switched antibody production.