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Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.
DeNardo and colleagues show that tissue-resident macrophages (TRMs) have a protective role during pancreas inflammation by triggering the activation of fibroblasts, but that TRM-driven fibrosis drives pancreas cancer pathogenesis.
In inflammation, some regulatory T (Treg) cells lose FoxP3 expression and become exTreg cells. Ley and colleagues mapped mouse Treg and exTreg cell transcriptomes to a human peripheral blood mononuclear cell single-cell RNA-sequencing dataset with surface markers (CITE-seq) and identify human exTreg cells as cytotoxic CD4+ T cells.
Rudloff et al. examine the kinetics of CD8+ T cell dysfunction/exhaustion. Tumor-specific CD8+ T cells in the tumor environment exhibit epigenetic modifications within hours, before cell division. The findings suggest a temporal relationship between tumor antigen exposure, chromatin remodeling and dysfunction ‘imprinting’.
Sen et al. provide in-depth temporal multi-omic analyses with single-cell RNA-sequencing (scRNA-seq) profiles of nuclear factor kappa B (NF-κB)-regulated gene expression in B cells upon B cell receptor (BCR) activation. Their findings reveal distinct kinetic patterns of gene expression mediated by RelA and Rel and functional antagonism between the closely related NF-κB subunits.
Chimeric antigen receptor (CAR)-T cells may become exhausted, non-functional or deplete their target cells of antigen, limiting their efficacy. Chen and colleagues fuse the CTLA-4 cytoplasmic tail to a CAR, which compromises trogocytosis and increases the functional capacity of CAR-T cells.
As the Plasmodium species that cause malaria replicate in the liver, Heath and colleagues designed mRNA vaccines to limit infection by inducing liver-resident memory T cells. Efficacy was observed in mice, including in hosts with previous blood-stage infection.
Basu et al. find that the transcription factor ThPOK is not restricted to T cells, as it also is expressed in myeloid cell progenitors and contributes to the lineage choice of monocyte-dendritic cells as opposed to neutrophils.
Young children frequently encounter respiratory pathogens that elicit immune responses in developing lungs. Farber and colleagues examine rare lung tissue samples obtained from pediatric organ donors and find age-dependent formation of bronchus-associated lymphoid tissue (BALT), which peaks at 3 years of age and dissipates thereafter. Profiling of BALT lymphocytes indicates that repertoire and functional differences exist between the lung, draining lymph nodes and circulating cells.
Tolar and colleagues describe how differential expression of CR2 by spatially distinct follicular dendritic cells regulates antigen retention in germinal centers of draining lymph nodes.
Establishment of antiviral immune responses depends on dendritic cells (DCs), but how transitional DCs compare with other DC subsets in this regard is unclear. Here the authors show the origins of these cells and their proinflammatory function during viral infection.
In cancer, neoantigen (NeoAg)-specific CD8+ T cells capable of direct tumor recognition have been extensively studied but little is known of the role of NeoAg-specific CD4+ T cells. Here Schoenberger and colleagues analyze an oligoclonal CD4+ T cell response to a naturally arising murine tumor NeoAg at the level of TCR usage and functionality.
Virtual memory T cells have antimicrobial functions but whether they can contribute to inflammatory pathology is unclear. Here the authors show that a subset of CD8+ T cells that originates from virtual memory T cells upon cytokine stimulation can drive the chronic inflammatory disease alopecia areata via innate-like cytotoxic effector functions.
Greter and colleagues identify a population of CD11c+F4/80+CD64+MHCII+CX3CR1+ macrophages in the mouse mammary gland that is induced by lactation and resembles several subsets of macrophages detected in human milk.
Kaplonek et al. provide a prospective look at ChAdOx1 nCoV-19-vaccinated individuals who go on to experience breakthrough COVID infections. They report an antibody Fc profile characterized by higher FcgR2b and reduced Fcgr3b for individuals who are more susceptible to breakthrough infections.
Here, the authors use computational screening and a chemogenetic analysis of transgenic mice to show that Gαs-coupled G-protein-coupled receptors on exhausted CD8+ T cells are involved in suppression of effector functions and inhibition of the protective effects of immune checkpoint immunotherapy.
Human leukocyte antigen (HLA)-E binds epitopes derived from HLA-A, HLA-B, HLA-C and HLA-G signal peptides (SPs) and serves as a ligand for CD94/NKG2A and CD94/NKG2C receptors. Carrington and colleagues provide comprehensive analysis of classical HLA class I SP variants and show that these can determine CD94/NKG2–HLA-E engagement.
Choi et al. show that infiltrating CCR2+ monocytes, by provision of IL-6, instruct tissue-resident microglia to become ‘repair-associated microglia’ following intracerebral hemorrhage, promoting cerebrovascular repair and neurological recovery.