The Journal of Experimental Medicine

Paludan, Søren R.;Cherry, Sara

doi: 10.1084/jem.20260871pmid: N/A

Hantavirus disease illustrates the complexity of infectious diseases and puts spotlight on the need to understand the processes driving pathology and those that can prevent or mitigate disease. This Viewpoint argues that improved treatments of viral diseases will require a combination of pathogenesis-guided strategies addressing the different phases of disease, including viral replication, tissue dysfunction, and damaging immune amplification.

Mínguez-Martínez, Jorge;Porcuna, Jesús;Casablanca, Laura;Gómez, Manuel J.;Aghelpasand, Hooman;Höjer, Pontus;García-Fojeda, Belén;Núñez, Vanessa;Torroja, Carlos;Mühleder, Severin;Gustafsson, Charlotte;Fischer, Thierry;Benedito, Rui;Casals, Cristina;Månsson, Robert;Sánchez-Cabo, Fátima;Ricote, Mercedes

doi: 10.1084/jem.20242085pmid: 42228021

Tissue-resident macrophages receive signals from their microenvironment that coordinate the activity of transcription factors (TFs) to establish distinct transcriptional profiles and identities. However, the molecular mechanisms whereby interactions with other cells of the niche imprint a distinct macrophage identity remain poorly understood. Here, we report that retinoid X receptors (RXRs) determine the differentiation and identity of alveolar macrophages (AM) by regulating chromatin accessibility and transcriptional activity of AM-core and function genes, enabling PPARγ-dependent programs. AM differentiation and maintenance in vivo require RXR upregulation in response to tissue-derived δ-like canonical Notch ligand 4 (DLL4), GM-CSF, and TGF β (TGFβ). Interplay among these signals leads to cooperation between RXRα, RBPJ, STAT5, and SMAD4 for the transcriptional and epigenetic regulation of key AM-core genes. These results underscore the role of RXRs as key TFs that cooperate with other regulatory elements to establish the AM population and determine AM identity.

Bruand, Marine;Srivastava, Divyanshu;Petruzzella, Aaron;Petit, Maxime;Mahfoud, Samantha;Katanayeva, Natalya;Kasapoglu, Asli;Landragin, Camille;Tavernari, Daniele;Balli, Eleni;Ciriello, Giovanni;Petrova, Tatiana V.;Oricchio, Elisa

doi: 10.1084/jem.20252463pmid: N/A

B cells mature into antibody-secreting cells by antigen processing and presentation and undergo productive germinal center (GC) reactions in secondary lymphoid organs. In solid tumors, antigen presentation and local anti-tumor humoral immunity can arise through the formation of GC-like tertiary lymphoid structures (TLS). Here, we show that cathepsin S activity is essential to form mature GC and TLS by regulating the communication of B cells with CD4+ Tfh cells and follicular dendritic cells. The absence of cathepsin S activity impairs B cells’ affinity maturation and high-affinity antibody production, and it limits the formation of TLS in lung and colorectal cancers, accelerating tumor progression. Conversely, the expression of an overactive form of cathepsin S, CTSSY132D, which was identified in follicular lymphoma patients, induces an accumulation of proliferating GC B cells, predisposing to lymphoma development. Overall, cathepsin S plays a nonredundant role in B cells, where maintaining its balanced activity is crucial to prevent lymphomagenesis and develop effective humoral immune responses.

Ma, Xiaonan;Guo, Henan;Jia, Yuting;Yin, Na;Peng, Min

doi: 10.1084/jem.20252687pmid: N/A

Memory CD8 T cells (TMEM) and exhausted CD8 T cells (TEX) are essential for host defense against infection and cancer, yet their therapeutic potential is often limited by insufficient persistence and sustained functional capacity. Strategies to enhance the longevity of both populations remain scarce. Here, we demonstrate that ablation of UBE2F, a neddylation E2 enzyme, induces a resilience program in CD8 T cells that operates across both TMEM and TEX compartments, resulting in improved viral and tumor control. This resilience state is characterized by enhanced self-renewal and survival without perturbing the conventional CD8 T cell differentiation trajectories. Mechanistically, UBE2F deficiency inhibited neddylation of CUL5, leading to accumulation of JUNB and upregulation of IL-2Rβ. The increased IL-2Rβ expression hypersensitizes CD8 T cells to physiological IL-15, thereby conferring the resilience features. Together, these findings identify the UBE2F–CUL5–JUNB–IL-2Rβ axis as a conserved posttranslational mechanism regulating CD8 T cell longevity across memory and exhausted states, providing a novel strategy for enhancing antiviral and antitumor immunity.

Cody, Evan W.;Ningoo, Mehek;Monga, Isha;Tsankov, Alexander M.;Muramatsu, Hiromi;Pardi, Norbert;Fribourg, Miguel;Heeger, Peter S.;Dominguez-Sola, David

doi: 10.1084/jem.20251048pmid: N/A

Memory B cell (Bmem) survival is essential for guarding against reinfection, yet processes ensuring their longevity remain unclear. As decay-accelerating factor (DAF, CD55), a negative regulator of complement activation, is requisitely downregulated on germinal center B cells and is reexpressed on Bmem, we investigated the effects of deleting DAF on murine (B1-8hi) Bmem in competitive settings. Kinetic analysis showed a progressive reduction in DAF−/− Bmem numbers over 6 wk, without affecting Bmem production, pool size, or their ability to respond to rechallenge. Following transfer into unimmunized hosts, wild-type Bmem proliferated to maintain stable Bmem pool sizes, outcompeting DAF−/− Bmem, reflecting homeostatic proliferation. Reduced proliferation and increased cell death in DAF−/− Bmem associated with transcriptional differences in metabolism and migration pathways. Wild-type Bmem proliferation increased in C3−/− hosts, and vaccination with a heterologous antigen, which induces local complement activation, locally inhibited bystander B1-8hi Bmem proliferation. Thus, complement-dependent regulation of Bmem homeostatic proliferation influences Bmem longevity and repertoire composition in mice.

Blanco-Domínguez, Rafael;Vaz-Pinto, André Miguel;Barros, Leandro;Lopes, Noella;Henriques-Alves, Beatriz;Carreira, Mariana;Labão-Almeida, Carlos;Ribot, Julie C.;Bernardes, Gonçalo J.L.;Silva-Santos, Bruno;Mensurado, Sofia

doi: 10.1084/jem.20252133pmid: N/A

Regulatory T (Treg) cells are potent immunosuppressors of conventional αβ T cells in the tumor microenvironment, but how they may affect innate-like γδ T cells remains poorly understood. Here, we show that induced Treg depletion in mice selectively unleashes IFNγ-producing γδ T cells, which are required for tumor control in an orthotopic breast cancer model. Treg cells outcompete IFNγ+ γδ T cells for IL-2 due to increased expression of the high-affinity IL-2 receptor, thereby limiting the proliferation and effector functions of IFNγ+ γδ T cells. Consistently, in vivo neutralization of IL-2 alongside Treg depletion abrogates the induction of IFNγ+ γδ T cell responses, whereas administration of an IL-2Rβγc agonist circumvents Treg-mediated suppression and enhances tumor control. Finally, Treg cells also inhibit endogenous and expanded human γδ T-cells, which can be rescued by IL-2Rβγc agonism to enhance therapeutic responses in xenografted mice. Thus, bypassing Treg-mediated suppression may improve the outcome of γδ T cell–based immunotherapies.

Keith, Yuki Honda;Duchini, Emily;Lin, Xufeng;Kyaw, Wunna;Weninger, Felix G.P.;Dhenni, Rama;Telfser, Aiden Josiah;Grootveld, Abigail K.;Barkauskas, Deborah;Fontaine-Titley, Angela;Tikoo, Shweta;Jain, Rohit;Weninger, Wolfgang;Frew, John W.;Deenick, Elissa K.;Brink, Robert;Martin, Linda K.;Chtanova, Tatyana;Goldstein, Leonard D.;Scolyer, Richard A.;Long, Georgina V.;Palendira, Umaimainthan;Phan, Tri Giang

doi: 10.1084/jem.20252239pmid: N/A

Macrophages in the skin reside in multiple distinct layers and perform various functions. Here, we show that CD169+ macrophages reside in the hypodermis and comprise the major skin myeloid cell population in the steady state. In a syngeneic melanoma model, CD169+ macrophages encapsulate growing melanomas and directly suppress their growth. CSF1R blockade depleted CD169+ macrophages in tumors and resulted in unrestrained growth. This local containment of tumor growth in the skin was independent of CD169+ subcapsular sinus macrophages in the tumor-draining lymph node and did not require B or T cells. Intravital imaging revealed engulfment and ingestion of live tumor cells by CD169+ macrophages. This phagocytosis did not require the phosphatidylserine receptor MERTK. CD169+ macrophages are also enriched in the hypodermis in skin biopsies from healthy human skin and melanoma. These data identify tissue-resident CD169+ macrophages as a potential cellular target to achieve innate immune containment and reinforce adaptive immune control of tumors.

Roci, Irena;Kim, Jaeryung; de Korodi, Kelly;Wyss, Tania;Bernier-Latmani, Jeremiah;Arroz-Madeira, Silvia;González-Loyola, Alejandra;Bovay, Esther;Grenningloh, Nadia;Schoofs, Hans;Jeon, Noo Li;Giampietro, Costanza;Mäkinen, Taija;Noël, Agnès;Petrova, Tatiana V.

doi: 10.1084/jem.20250506pmid: N/A

Intestinal lymphatic vessels are essential for dietary lipid absorption and immune cell trafficking. Villus lymphatic capillaries, lacteals, undergo continuous VEGF-C–dependent renewal to function in a hyperosmolar, inflammatory environment exposed to dietary and microbial by-products. To define mechanisms underlying this adaptation, we integrated new and published single-cell RNA-sequencing datasets of murine small intestinal lymphatic endothelial cells (LECs). Lacteal LECs resembled Ptx3+ immune-interacting LECs and were characterized by high expression of water channel AQP1. LEC-specific Aqp1 deletion reduced lacteal length, impaired lipid uptake, and limited weight gain on a high-fat diet, while mosaic deletion revealed a cell-autonomous requirement for AQP1 in LEC positioning at hyperosmolar tip regions. AQP1 promoted LEC migration under hyperosmotic stress by preserving cytoskeletal and junctional remodeling and alleviating osmotic stress–induced transcriptional programs. AQP1 was upregulated during inflammatory remodeling in lymphedema and lymphatic malformations, but not during embryonic lymphangiogenesis. These findings link lacteal regeneration to inflammatory lymphatic remodeling and highlight tissue osmolarity as a biophysical determinant of postnatal lymphangiogenesis.

Nunes de Almeida, Francisca;Vasciaveo, Alessandro;Giacobbe, Arianna; Di Bernardo, Matteo;Zou, Min;Antao, Ainsley Mike; de Brot, Simone;Rodriguez-Calero, Antonio;Chui, Alexander;Wang, Alexander L.E.;Floc’h, Nicolas;Kim, Jaime Y.;Park, Soonbum;Afari, Stephanie N.;Mukhammadov, Timur;Ortega, Nicholas;Josyula, Sai Sampath;Arriaga, Juan Martin;Wang, Jingqiang;Lu, Jinqiu;Shen, Michael M.;Rubin, Mark A.;Califano, Andrea;Abate-Shen, Cory

doi: 10.1084/jem.20241484pmid: 42207152

Although most prostate tumors are relatively indolent, advanced disease can progress to aggressive, often lethal variants, including neuroendocrine prostate cancer (NEPC). To identify drivers of aggressive prostate cancer, we used Sleeping Beauty (SB) transposon mutagenesis in a mouse model having prostate-specific loss of Pten and Tp53 (NPp53 mice). Compared with control NPp53-SB(−) mice, experimental NPp53-SB(+) mice developed more aggressive tumors with increased metastasis. Notably, NPp53-SB(+) mice exhibited NEPC phenotypes with transcriptomic features that recapitulate human NEPC. Analysis of recurrent common insertion sites (CIS) and associated genes (CIS genes) identified genes differentially expressed between NEPC and non-NEPC tumors. Analysis of NEPC-enriched CIS genes by cross-species integration of genomic and transcriptomic data prioritized sirtuin 1 (Sirt1) as a candidate mechanistic determinant of NEPC. Gain- and loss-of-function studies in human prostate cancer cells and mouse NEPC organoids confirmed that SIRT1 promotes NEPC, while pharmacological inhibition suppresses it. Thus, integration of cross-species analyses with an unbiased forward genetic screen uncovered novel drivers of NEPC.