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The APOE4 allele is a major genetic risk factor for the development of late-onset Alzheimer’s disease (AD). In this manuscript, Butovsky and colleagues suggest that APOE4 impairs the microglial response in AD by inducing TGFβ-mediated checkpoints.
Here the authors use single cell profiling of T cells across the human lifespan to show that a suboptimal TCR shift in T cells as we enter older age results in a molecular signature that resembles that of T cells from newborns and children.
Satija and colleagues use multimodal sequencing technologies and cross-modality integration tools to define distinct subpopulations of CD8+ T cells that are predictive of COVID-19 severity.
Wherry and colleagues define the kinetics of vaccine-primed recall immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection, highlighting rapid activation of memory T cells and broadly enhanced immune responses in previously vaccinated individuals.
The mechanisms by which noncoding genetic variation shapes tissue macrophage phenotypic diversity remain obscure. Glass and colleagues define cell-intrinsic and environmental effects contributing to genetic control of Kupffer cell transcription.
Iron metabolism has been shown to play an important role in the development and function of the immune system, but its role in ILC3s is unclear. Here the authors show that CD71-mediated iron metabolism controls ILC3 proliferation and the host response to Citrobacterrodentium infection and CD71 expression is regulated by Ahr signaling.
Santosa et al. show that IRF4 is upregulated upon NK cell activation and acts as a signal integrator for the differentiation and expansion of mouse cytomegalovirus-specific NK cells by partly controlling nutrient uptake required for adaptive NK cell responses.
Chi and colleagues identify brain-resident CXCR6+PD-1+CD8+ T cells that interact with resident microglia to limit immune-mediated pathology in a mouse model of Alzheimer’s disease.
Here the authors show that TFPI2 promotes glioblastoma stem cell self-renewal and connects stemness to microglia immunosuppression, plus targeting TFPI2-mediated glioblastoma stem cell–microglia symbiosis inhibits tumor growth and synergizes with anti-PD1 therapy in glioblastoma.
Zikherman and colleagues uncover a new mechanism by which B cells recognize virus-like antigen display as a stand-alone danger signal (independent of nucleic acid cargo) that does not rely exclusively on avidity and BCR cross-linking.
The DNA-binding domains of transcription factors have been well characterized, but whether their intrinsically disordered regions control cell fate is unclear. Here, the authors show the functional and mechanistic importance of an intrinsically disordered region of TCF-1 in T cell development.
Thomas and colleagues examine preinfection baseline parameters of cellular and serologic immunity. Their findings collectively show that peripheral cell composition provides better correlates of immune protection from symptomatic influenza infection than vaccination, demographics or serology alone.
Here, the authors show that short-term consumption of energy-dense diets deficient in fiber, similar to eating patterns for many people today, results in a transient depression of the mucosal and systemic immune systems such that susceptibility to bacterial infection is increased.
Runx family proteins direct lineage-fate decisions in multiple cell types. Here, Rothenberg and colleagues show how limited Runx protein abundance dictates T cell lineage developmental kinetics through competition for binding by its protein interaction partners.
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.