Journal of Experimental Medicine最新文献

Macrophage antibacterial activity requires mtROS production. The specific gene(s) that participates in the mtROS-mediated antibacterial process remains unclear. We showed that Listeria and Salmonella infections in human and mouse macrophages increased mtDNA copy number with which dictates antibacterial activity. Interestingly, adenylate kinase 4 (Ak4) expression was upregulated in macrophages after infection. Ak4 KO mice as well as macrophage-specific Ak4 KO mice became highly susceptible to bacterial infections. Ak4 is critical for the increase of mtDNA synthesis and mitochondrial mass in macrophages after bacterial infection. Biochemically, Ak4 transfers a phosphate group from ATP/GTP to (d)AMP for (d)ADP formation, and the K18A and G89S/A166D mutations abolished this function. Our results suggest that induction of Ak4 after infection produces more dADP, whose conversion to dATP in mitochondria supports mtDNA synthesis and the subsequent increase of mtROS production. Loss of this metabolic coupling in Ak4 KO macrophages diminishes antibacterial activity. Our findings highlight the vital role of Ak4 in macrophage defense against pathogenic bacteria.

Monocytes populate tissues when local niches are depleted of tissue-resident macrophages, yet the tissue-derived signals controlling monocyte-to-macrophage differentiation are largely undefined. Here, we discovered that the oxysterol receptor GPR183 positions monocytes to sense niche signals that induce lung macrophage differentiation. We found that interstitial macrophages that continuously turn over express the oxysterol receptor GPR183, whereas alveolar macrophages that derive from embryonic progenitors and slowly turn over did not. Models of conditional tissue-resident macrophage depletion showed that newcomer monocyte-derived macrophages expressed GPR183 along their differentiation trajectory. Recruited GPR183+ monocytes interacted with fibroblasts and lack of GPR183 caused defective lung macrophage differentiation. Single-cell RNA analysis over time identified lung fibroblasts as the source of the GPR183 ligand 7α,25-dihydroxycholesterol in the empty niche. Our findings identify oxysterols as instructive signals for tissue-resident macrophage development from monocytes.

Humans are disomic. At birth, all nucleated cells in the body have the same genetic material, composed of 22 pairs of autosomes and a pair of sex chromosomes. Half the chromosomes are maternal, and half are paternal. It is thought that the two copies of autosomal genes are equally transcribed and translated in a given cell. This notion, based on Mendelian genetics, has guided the identification of genetic variants capable of causing disease for a century. These variants have been classified as displaying dominant or recessive inheritance. The term "penetrance" was coined to explain why some individuals carrying disease-causing variants do not develop the disease. Differences in penetrance are often assumed to be due to largely unproven effects of the environment, polygenic effects, and/or mosaicism. More recently, autosomal random monoallelic expression (aRMAE)-a phenomenon in which one of the two parental alleles of a gene is more strongly or exclusively expressed in some, but not all, cells-has been put forward to account for the incomplete penetrance observed in a growing number of genetic conditions. Here, we review aRMAE from historical, biochemical, genetic, epigenetic, and disease-influencing perspectives and propose a new framework.

NIK (Map3k14) is a central regulator of noncanonical NF-κB signaling and immune homeostasis. Mutations in this kinase are linked to autoimmune disorders, including multiple sclerosis (MS). Both germline and T cell-specific deletion of NIK had been demonstrated previously to be associated with resistance to developing experimental autoimmune encephalomyelitis (EAE), an animal model for MS. In this study, we show that NIK expression by circulating myeloid cells is crucial for EAE development. Mechanistically, we found starkly reduced priming of neuroantigen-specific T cells in the absence of NIK in CX3CR1+ cells. This reduction was associated with dysregulated expression of genes involved in antigen presentation and cell migration, as well as decreased IL-23 production. Notably, T cells primed by NIK-deficient myeloid cells regained their ability to induce EAE when incubated with IL-23 before being transferred into RagKO mice. Our data underline the crucial role of NIK in enabling myeloid cells to function effectively as antigen-presenting cells.

Myeloid cells are present in neoplastic tissues from the earliest stages of transformation through to fully developed tumors. However, their intrinsic dynamism and plasticity make them difficult to target therapeutically. Emerging technologies are uncovering previously unrecognized cellular states and functions, thus reshaping our understanding of myeloid cell biology beyond their traditional inflammatory roles. This review discusses recent advances in identifying tumor-specific cues, tissue structural components, and the temporal modulation of neutrophil and macrophage programs in tumors, which are influenced by both cell-intrinsic and systemic signals. By integrating molecular, environmental, and time-dependent aspects of myeloid biology, we discuss here our understanding of their functional diversity and inform the development of future cancer therapy strategies.

Immune checkpoint inhibitors (ICIs) improve cancer survival but can trigger immune-related adverse events. Among these, fulminant myocarditis is an often fatal complication with limited therapies. We developed a mouse model employing cardiomyocyte-restricted antigen expression to define how ICIs drive cardiac autoimmunity. Combined cytotoxic T cell antigen-4 (αCTLA-4) and programmed death-1 (αPD-1) blockade uniquely induced robust expansion of antigen-specific CD8 T cells, myocardial inflammation, and lethal arrhythmias. PD-1 blockade alone permitted the priming and effector differentiation of naive autoreactive CD8 T cells, whereas concomitant CTLA-4 inhibition amplified cardiac pathology. Unexpectedly, myocardial injury was independent of perforin-mediated cytotoxicity but critically depended on T cell-derived TNF, which promoted myeloid recruitment, cytokine production, and arrhythmogenesis. Genetic ablation of CD8 T cell-derived tumor necrosis factor (TNF) or TNF receptor 2 (TNFR2) blockade prevented cardiotoxicity while preserving antitumor efficacy. These findings establish a TNF-TNFR2-driven inflammatory circuit downstream of autoreactive CD8 T cells as a central mechanism of ICI myocarditis and a strategy to uncouple cardiotoxicity from immunotherapy benefits.

In this issue of JEM, Golec et al. (https://doi.org/10.1084/jem.20252154) report that a mutation of PI-3 kinase underlying activated PI3K δ syndrome (APDS) impairs type 2 immunity. Surprisingly, mice with this mutation have disordered responses to allergic insults, with enhanced production of IFN-γ and a decrease in Th2 cytokines.

Innate immune cells can retain molecular imprints of past encounters long after the initial stimulus has ceased. In this issue, Gorin et al. (https://doi.org/10.1084/jem.20250976) reveal an unexpected mechanism by which IFN-γ sustains trained immune states through prolonged signaling driven by cytokine retention at the cell surface.

Autoimmune hepatitis (AIH) is a severe, chronic disease where IgG elevation and autoantibody profile are defining features. However, linking autoantibodies to AIH pathogenesis remains elusive. We employed phage-display immunoprecipitation sequencing and uncovered a novel humoral signature specific to AIH. Embedded within this signature were antibodies against the known AIH autoantigen SLA/LP and novel reactivities to disco-interacting protein 2 homolog A (DIP2A), and the relaxin family peptide receptor 1 (RXFP1). Fine mapping of the DIP2A epitope revealed preferential enrichment for a nearly identical 9-amino acid sequence derived from the U27 protein of human herpesvirus 6 (HHV6). Preincubation with the HHV6 epitope blocked DIP2A binding, consistent with cross-reactivity. AIH patients positive for anti-DIP2A had higher titers of HHV6 IgG, suggestive of reactivation. AIH patients had antibodies against the antifibrotic receptor, RXFP1, which inhibited relaxin-2 signaling in an IgG-dependent manner. These data provide evidence for a novel serological profile in AIH, linking HHV6 reactivation anti-RXFP1 antibodies to disease pathogenesis.