Ise et al. identify the plasma cell-prone LZ GC B cells whose generation relies on the amount of CD40 signal. Higher expression of ICAM-1 and SLAM in those cells facilitates more stable contacts with Tfh cells, suggesting that strength of Tfh-GC B cell interaction critically regulates formation of plasma cell precursors.
Epstein-Barr virus is a cancer-associated pathogen for which there is no vaccine. Snijder et al. isolate a monoclonal antibody that neutralizes infection of the major cell types infected by EBV. Structural analysis of the antibody-gH/gL glycoprotein complex reveals a key site of EBV vulnerability that may pave the way for a next-generation EBV vaccine.
It is unclear how quiescence is enforced in naive T cells, yet activation is allowed. Tu et al. show that TGF-β signaling maintains T cell quiescence. Strong TCR stimuli reduce TβRI expression and consequently abolish TGF-β signaling in T cells. TCR-mediated TβRI downregulation acts as a “third criterion” to fully activate T cells in addition to the “two-signal” model.
The adult bone marrow provides essential niches for hematopoietic stem cell (HSC) maintenance and differentiation, which are not fully understood. Here we review the currently known cellular and molecular components of the niche for hematopoietic stem cells and their progeny, highlight their heterogeneity and interdependency, and discuss some open questions in the field.
Chronic inflammatory diseases represent an increasing medical burden, yet neither tools to predict the individual disease course nor causal cures are at hand. We discuss opportunities for systems medicine to derive precise, individualized disease models and outline the European consortium SYSCID as part of the roadmap to clinical practice.
Alessandro Moretta passed away in his home in Genova at age of 64 on February 17th, 2018 after a 7-year-long fight against metastatic lung cancer. Despite the heavy chemo- and radio-therapy, he continued to successfully pursue his research, guide his coworkers, and write papers and research projects. Anti-PD1 therapy helped to provide a significant improvement of his disease in the last 3 years. Just 2 days before his death, Alessandro’s meeting with the University of Genova Rector Delegate was fundamental to obtain sufficient funding to maintain the PhD program in immunology, a program he recently accepted to direct.
The mechanisms underlying the maintenance and dysfunction of exhausted pDCs during chronic viral infection are unclear. Macal and Jo et al. find that exhausted pDCs are maintained by IFN-I and TLR7 signaling via multiple mechanisms, including inhibition of bone marrow pDC generation, sustained proliferation of exhausted pDCs, and promotion of pDC functional loss, the latter of which leads to impaired host defense to secondary infection.
c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells
c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4<sup>+</sup> T cells, Published online: 16 April 2018; doi:10.1038/s41590-018-0083-5
The transcription factor c-Maf controls IL-10 production in T cells. O’Garra and colleagues use systems and in vivo functional analysis of T cell subsets to reveal distinct context-specific roles for c-Maf.
Distinct myeloid cell subsets promote meningeal remodeling and vascular repair after mild traumatic brain injury
Distinct myeloid cell subsets promote meningeal remodeling and vascular repair after mild traumatic brain injury, Published online: 16 April 2018; doi:10.1038/s41590-018-0086-2
Meningeal vascular damage accompanies mild traumatic brain injury, which persists in a fraction of patients. McGavern and colleagues report that distinct myeloid cell subsets are temporally recruited to the wound site during tissue repair; however, re-injury at early time points impairs recovery.
Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling
Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling, Published online: 16 April 2018; doi:10.1038/s41590-018-0091-5
Harris and colleagues show that the cytokine TGF-β is required for colonization of the microglial niche and maintenance of central nervous system integrity. Acute loss of TGF-β leads to proinflammatory responses and fatal demyelinating disease.
Monomeric TCRs drive T cell antigen recognition
Monomeric TCRs drive T cell antigen recognition, Published online: 16 April 2018; doi:10.1038/s41590-018-0092-4
Higher-order TCRs have been postulated to maintain high antigen sensitivity and trigger signaling. Huppa and colleagues use various investigative techniques and find exclusively monomeric TCR–CD3 complexes that drive the recognition of antigenic pMHC.
The human body and its resident microbiota form a complex ecosystem, shaped by both inherited and environmental factors. The use of antibiotics represents an extreme example of environmental pressure and can broadly disrupt the microbial landscape. The benefits that antibiotics have brought to modern medicine are unquestionable; however, their overuse comes with consequences, including the potential for secondary infections by opportunistic pathogens and the spread of antibiotic resistance. Here, we discuss the implications of microbial dysbiosis driven by antibiotics, with a focus on potential links with allergy and asthma.
The inflammatory mechanism of psoriasis remains incompletely understood. In this issue, Xu et al. identified IL-25 as a key pathogenic factor regulating the proliferation of keratinocytes and psoriasis development in an autocrine expression manner.
The cGAS-STING pathway is required for host defense against DNA viruses. Wang et al. find that upon virus infection, Manganese (Mn2+) is released from organelles into the cytosol and facilitates the activation of cGAS and STING. Their findings identify a role for Mn in innate immune activation and host anti-viral defense.
Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells
Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells, Published online: 09 April 2018; doi:10.1038/s41590-018-0082-6
NK cells constrain infection by cytomegalovirus. Romagnani and colleagues show that human NKG2C+ NK cells recognize distinct HCMV UL40 viral peptides, which can vary among viral isolates. NKG2C+ NK cells thereby demonstrate adaptive-like recognition that can discriminate between closely related viral strains.
Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy.
Disrupting the balance between self-renewal and differentiation of HSCs leads to severe pathologic consequences. Xia et al. identify a circular RNA cia-cGAS that is highly expressed in the nucleus of LT-HSCs. Under homeostatic conditions, cia-cGAS binds DNA sensor cGAS to block its synthase activity, protecting dormant LT-HSCs from cGAS-mediated exhaustion.
TLR9 recognizes DNAs with unmethylated CpG motifs and activates innate immune responses. Ohto et al. identify another TLR9 binding motif, the 5′-xCx DNA motif, and determine the tertiary structure of TLR9 in complex with CpG and 5′-xCx DNAs to reveal a cooperative activation mechanism of TLR9 by two types of DNAs.
Mechanisms driving T cell exhaustion have not been understood. Li et al. demonstrate that B7S1 on tumor-infiltrating myeloid cells initiates exhaustion of activated CD8+ TILs through upregulating Eomes, thus proposing B7S1 as a promising target to enhance the efficacy of anti-PD-1 therapy.