bims-traimu 2025-02-02 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–02–02
thirteen papers selected by
Yantong Wan, Southern Medical University

Advancing veterinary vaccines design through trained immunity insights.
The Role of Dectin-1-Akt-RNF146 Pathway in β-Glucan Induced Immune Trained State of Monocyte in Sepsis.
BCG-Induced DNA Methylation Changes Improve Coronavirus Disease 2019 Vaccine Immunity Without Decreasing the Risk for Severe Acute Respiratory Syndrome Coronavirus 2 Infection.
HMGB1-mediated CIITA super-enhancers are critical for DC trained immunity in acute-to-chronic progression of allograft rejection.
Control of Mycobacterium tuberculosis infection in the elderly: Is there a role for epigenetic reprogramming reversal?
Schistosoma mansoni antigen induced innate immune memory features mitochondrial biogenesis and can be inhibited by ovarian produced hormones.
Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically.
Effect of Bacille Calmette-Guérin vaccination on immune responses to SARS-CoV-2 and COVID-19 vaccination.
Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection.
Single-Cell Landscape of Bronchoalveolar Lavage Fluid Identifies Specific Neutrophils during Septic Immunosuppression.
Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.
Mannose-modified exosomes loaded with MiR-23b-3p target alveolar macrophages to alleviate acute lung injury in Sepsis.
Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks.

Front Vet Sci. 2024 ;11 1524668

Advancing veterinary vaccines design through trained immunity insights.

Xin Wang, Guohua Yu.

  Trained immunity, characterized by long-term functional reprogramming of innate immune cells, offers promising new directions for veterinary vaccine development. This perspective examines how trained immunity can be integrated into veterinary vaccine design through metabolic reprogramming and epigenetic modifications. We analyze key molecular mechanisms, including the shift to aerobic glycolysis and sustained epigenetic changes, that enable enhanced immune responses. Strategic approaches for vaccine optimization are proposed, focusing on selecting effective trained immunity inducers, developing innovative adjuvant systems, and achieving synergistic enhancement of immune responses. While implementation challenges exist, including individual response variations and safety considerations, trained immunity-based vaccines show potential for providing broader protection against emerging pathogens. This approach could revolutionize veterinary vaccinology by offering enhanced efficacy and cross-protection against heterologous infections, particularly valuable for zoonotic disease control.

Keywords:  epigenetic modification; innate immune memory; metabolic reprogramming; trained immunity; veterinary vaccines

DOI:  https://doi.org/10.3389/fvets.2024.1524668
J Inflamm Res. 2025 ;18 1147-1165

The Role of Dectin-1-Akt-RNF146 Pathway in β-Glucan Induced Immune Trained State of Monocyte in Sepsis.

Chenyue Guo, Peiyao Xu, Wenchen Luo, Jinlin Zhang, Xingfeng Sun, Harry Hoang, Duan Ma, Dehua Wu, Jing Zhong, Changhong Miao.

   Background: Sepsis is regarded as a dysregulated immune response to infections. Recent study showed partially reversal of immunosuppression by trained immunity, which fosters an enhanced immune response towards a secondary challenge. However, the role of trained immunity in sepsis has not been fully understood.
Methods: We profiled the characteristics of peripheral blood mononuclear cells from septic patients using single-cell RNA sequencing (scRNA-seq) analyses. Murine double-hit models (pretreatment or post-treatment of β-glucan in septic mice) and murine monocyte/macrophage cell line RAW264.7 were used then.
Results: scRNA-seq revealed that Ring finger protein 146 (RNF146) and protein kinase B (Akt) were downregulated in the immunosuppression period of septic patients and were verified to be decreased in bone marrow and spleen monocytes from septic mice. While β-glucan pretreatment improved the immunosuppressed state in septic mice and increased dectin-1/Akt/RNF146 expressions in monocytes, along with the increased survival rate, inflammatory factors and aerobic glycolysis, indicating a change from immunosuppression to immune training. Moreover, RNF146 regulated dectin-1-Akt-mTOR signaling in the trained immune state of murine monocyte/macrophage RAW264.7 cell line and the expression of RNF146 was dependent on dectin-1-Akt activation. The inhibition of dectin-1 by its antagonist laminarin downregulated Akt-RNF146 signaling and partially reversed β-glucan induced trained immunity in septic mice.
Conclusion: RNF146 and Akt are downregulated in the immunosuppression period of sepsis, while increased after β-glucan pretreatment induced trained immunity in septic mice. Moreover, RNF146 regulates the immune trained state of monocyte through dectin-1-Akt-mTOR pathway, suggesting a possible target in reversal of immunosuppression in sepsis.

Keywords:  RNF146; immunosuppression; sepsis; trained immunity; β-glucan

DOI:  https://doi.org/10.2147/JIR.S482213
Open Forum Infect Dis. 2025 Jan;12(1): ofaf007

BCG-Induced DNA Methylation Changes Improve Coronavirus Disease 2019 Vaccine Immunity Without Decreasing the Risk for Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

Santiago Carrero Longlax, Kent J Koster, Ashish M Kamat, Marisa Lozano, Seth P Lerner, Rebecca Hannigan, Tomoki Nishiguchi, Abhimanyu, Daanish Sheikh, Malik Ladki, Alexandra Portillo, Amrit Koirala, Tajhal D Patel, Zoe Spieler, Aaron B Benjamin, Maxim Lebedev, Theresa U Ofili, Robert W Hutchison, George Udeani, Lynne A Opperman, Gabriel Neal, Anna M Mandalakas, Mihai G Netea, Moshe Arditi, Pablo Avalos, Sandra L Grimm, Cristian Coarfa, Jeffrey D Cirillo, Andrew R DiNardo.

   Background: The BCG vaccine induces trained immunity, an epigenetic-mediated increase in innate immune responsiveness. Therefore, this clinical trial evaluated if BCG-induced trained immunity could decrease coronavirus disease 2019 (COVID-19)-related frequency or severity.
Methods: A double-blind, placebo-controlled clinical trial of healthcare workers randomized participants to vaccination with BCG TICE or placebo (saline). Enrollment included 529 healthcare workers randomized to receive BCG or placebo. Primary analysis evaluated COVID-19 disease frequency, while secondary analysis evaluated coronavirus immunity in a subset of participants. Study enrollment ceased early in December 2020 following introduction of COVID-19-specific vaccines.
Results: Study enrollment was halted early, prior to reaching the targeted recruitment, and was not powered to detect a decrease in COVID-19 frequency. Symptomatic COVID-19 occurred in 21 of 263 and 10 of 266 participants in the BCG and placebo arms, respectively (P = .50, Fisher exact test). Participants vaccinated with BCG, but uninfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrated increased coronavirus vaccine immunity (increase spike-inducible levels of tumor necrosis factor, interleukin 6, and interleukin 1β) 12 months after BCG vaccination compared to participants receiving placebo. Immune responsiveness to SARS-CoV-2 antigens correlated with BCG-induced DNA methylation changes.
Conclusions: Due to early study closure, the study was not powered to evaluate COVID-19 frequency. Secondary analysis demonstrated that 12 months following vaccination, BCG increased coronavirus vaccine immunity compared to those who did not receive BCG. This increase in COVID-19 vaccine immunity correlated with BCG-induced DNA methylation changes.

Keywords:  BCG vaccine; COVID-19; DNA methylation; epigenetics; innate training

DOI:  https://doi.org/10.1093/ofid/ofaf007
Am J Transplant. 2025 Jan 28. pii: S1600-6135(25)00043-7. [Epub ahead of print]

HMGB1-mediated CIITA super-enhancers are critical for DC trained immunity in acute-to-chronic progression of allograft rejection.

Lingjuan Sun, Xiangli Zhao, Xiaosheng Tan, Liu Song, Zhibo Ma, Jingzeng Wang, Peixiang Lan, Song Chen, Gang Chen.

  Chronic allograft rejection is mainly mediated by indirect recognition. Dendritic cells (DCs), as the major antigen-presenting cells in indirect recognition, exhibit an enhanced antigen-presenting ability in chronic rejection, but the specific mechanism is still unclear. Here, we found that pretreatment with high mobility group box-1 protein (HMGB1) in vivo can induce trained immunity in DCs. These trained DCs demonstrated an enhanced ability to present alloantigen, accelerating allograft rejection in a CTLA4-Ig-induced chronic rejection model by upregulating the expression of MHC-II and class II major histocompatibility complex transactivator (CIITA) molecules. Mechanistically, we found that HMGB1 promoted the formation of super-enhancers (SEs) of CIITA, epigenetically reprogramming DCs and promoting trained immunity. The SEs inhibitor JQ1 reduced the expression of CIITA and MHC-II in DCs, thereby delaying the occurrence of chronic rejection. Interestingly, we identified HMGB1 as a specific inducer of SE formation in a newly named SEa region of CIITA. Targeted knockout of the CIITA's SEa region inhibited HMGB1-induced trained immunity in DCs. Taken together, our data confirm that HMGB1 can induce the formation of the SEs of CIITA, promote trained immunity in DCs, and accelerate allograft rejection, thus offering a new potential target for the treatment of chronic rejection.

Keywords:  CIITA; DC; HMGB1; chronic rejection; super enhancer; trained immunity

DOI:  https://doi.org/10.1016/j.ajt.2025.01.037
Biofactors. 2025 Jan-Feb;51(1):51(1): e2151

Control of Mycobacterium tuberculosis infection in the elderly: Is there a role for epigenetic reprogramming reversal?

Dámaris P Romero-Rodríguez, Carlos A Díaz-Alvarado, Héctor Isaac Rocha-González, Esmeralda Juárez.

  With the increase in the elderly population worldwide, the number of subjects suffering from tuberculosis (TB) has shown an increased prevalence in this group. Immunosenescence is essential in this phenomenon because it may reactivate the lesions and render their adaptive immunity dysfunctional. In addition, inflammation in the lungs of the elderly subjects is also dysfunctional. Although effective drugs are available, they are often tolerated inadequately, reducing adherence to the therapy and leading to therapeutic failure. Comorbidities, poor general health status, and other medications may lead to increased drug adverse reactions and reduced adherence to treatment in the elderly. Hence, older adults require an individualized approach for better outcomes. Trained immunity, which involves epigenetic reprogramming, may contribute to balancing the dysfunction of innate and adaptive immunity in older people. This review analyzes the relationship between inflammation, age, and Mycobacterium tuberculosis. Moreover, we hypothesize that immunomodulation using trained immunity activators will help reduce inflammation while enhancing antimicrobial responses in the elderly. Understanding immunomodulation's molecular and physiological effects will lead to informed decisions about TB prevention and treatment strategies uniquely designed for the elderly.

Keywords:  elderly; epigenetic reprogramming; immunosenescence; trained immunity; tuberculosis

DOI:  https://doi.org/10.1002/biof.2151
bioRxiv. 2025 Jan 18. pii: 2025.01.14.632838. [Epub ahead of print]

Schistosoma mansoni antigen induced innate immune memory features mitochondrial biogenesis and can be inhibited by ovarian produced hormones.

Juan Marcos Oviedo, Diana Cortes-Selva, Marco Marchetti, Lauren Gordon, Lisa Gibbs, J Alan Maschek, James Cox, Seth Frietze, Eyal Amiel, Keke C Fairfax.

  We have previously identified that S. mansoni infection induces a unique form of myeloid training that protects male but not female mice from high fat diet induced disease. Here we demonstrate that ovarian derived hormones account for this sex specific difference. Ovariectomy of females prior to infection permits metabolic reprogramming of the myeloid lineage, with BMDM exhibiting carbon source flexibility for cellular respiration, and mice protected from systemic metabolic disease. The innate training phenotype of infection can be replicated by in vivo injection of SEA, and by exposure of bone marrow to SEA in culture prior to macrophage differentiation (Day 0). This protective phenotype is linked to increased chromatin accessibility of lipid and mitochondrial pathways in BMDM including Nrf1 and Tfam, as well as mitochondrial biogenesis. This work provides evidence that S. mansoni antigens induce a unique form of innate training inhibited by ovarian-derived hormones in females.

Keywords:  Myeloid lineage; Schistosoma mansoni; biological sex; innate training; macrophage metabolism; metabolic disease

DOI:  https://doi.org/10.1101/2025.01.14.632838
Nat Commun. 2025 Jan 25. 16(1): 1030

Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically.

Mingming Zhao, Dragana Jankovic, Verena M Link, Camila Oliveira Silva Souza, Katherine M Hornick, Oyebola Oyesola, Yasmine Belkaid, Justin Lack, Png Loke.

How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.

DOI: https://doi.org/10.1038/s41467-025-56379-8
Clin Transl Immunology. 2025 ;14(1): e70023

Effect of Bacille Calmette-Guérin vaccination on immune responses to SARS-CoV-2 and COVID-19 vaccination.

BRACE Trial Consortium Group

   Objectives: Bacille Calmette-Guérin (BCG) vaccination has off-target effects on disease risk for unrelated infections and immune responses to vaccines. This study aimed to determine the immunomodulatory effects of BCG vaccination on immune responses to vaccines against SARS-CoV-2.
Methods: Blood samples, from a subset of 275 SARS-CoV-2-naïve healthcare workers randomised to BCG vaccination (BCG group) or no BCG vaccination (Control group) in the BRACE trial, were collected before and 28 days after the primary course (two doses) of ChAdOx1-S (Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) vaccination. SARS-CoV-2-specific antibodies were measured using ELISA and multiplex bead array, whole blood cytokine responses to γ-irradiated SARS-CoV-2 (iSARS) stimulation were measured by multiplex bead array, and SARS-CoV-2-specific T-cell responses were measured by activation-induced marker and intracellular cytokine staining assays.
Results: After randomisation (mean 11 months) but prior to COVID-19 vaccination, the BCG group had lower cytokine responses to iSARS stimulation than the Control group. After two doses of ChAdOx1-S, differences in iSARS-induced cytokine responses between the BCG group and Control group were found for three cytokines (CTACK, TRAIL and VEGF). No differences were found between the groups after BNT162b2 vaccination. There were also no differences between the BCG and Control groups in COVID-19 vaccine-induced antigen-specific antibody responses, T-cell activation or T-cell cytokine production.
Conclusion: BCG vaccination induced a broad and persistent reduction in ex vivo cytokine responses to SARS-CoV-2. Following COVID-19 vaccination, this effect was abrogated, and BCG vaccination did not influence adaptive immune responses to COVID-19 vaccine antigens.

Keywords:  Bacille Calmette–Guérin (BCG) vaccine; COVID‐19; heterologous; immunity; immunomodulation

DOI:  https://doi.org/10.1002/cti2.70023
Sci Transl Med. 2025 Jan 29. 17(783): eadq1086

Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection.

Stanford COVID-19 Biobank

At this stage in the COVID-19 pandemic, most infections are "breakthrough" infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.

DOI: https://doi.org/10.1126/scitranslmed.adq1086
Adv Sci (Weinh). 2025 Jan 30. e2406218

Single-Cell Landscape of Bronchoalveolar Lavage Fluid Identifies Specific Neutrophils during Septic Immunosuppression.

Rong Shen, Yi Jiang, Guanglong Liu, Shenjia Gao, Hao Sun, Xinyi Wu, Jiahui Gu, Han Wu, Ke Mo, Xing Niu, Ronen Ben-Ami, Wanjing Shang, Jie Zhang, Jun Wang, Changhong Miao, Zhizhang Wang, Wankun Chen.

  Sepsis-induced immunosuppression is related to increased susceptibility to secondary infections and death. Lung is the most vulnerable target organ in sepsis, but the understanding of the pulmonary immunosuppression state is still limited. Here, single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) is performed to map the landscape of immune cells, revealing a neutrophil-driven immunosuppressive program in the lungs of patients with immunosuppressive sepsis. Although immunosuppressive genes are upregulated in different immune cells, only neutrophils dramatically increase in the BALF of patients in immunosuppressive phase of sepsis. Five neutrophil subpopulations in BALF are identified, among which CXCR2+ and CD274 (PD-L1 coding gene)+IL1RN+ neutrophil subpopulations increased significantly during septic immunosuppression. Interestingly, a developmental trajectory from CXCR2+ to CD274+IL1RN+ neutrophil subpopulation is disclosed. Moreover, the therapeutic effect of CXCR2 blockade is observed on the survival of septic mice, along with a decreased number of PD-L1+ neutrophils. Taken together, the CXCR2+ neutrophil subpopulation is discovered as a contributor to immunosuppression in sepsis and identified it as a potential therapeutic target in sepsis treatment.

Keywords:  CXCR2; bronchoalveolar lavage fluid; neutrophils; sepsis; single‐cell RNA sequencing

DOI:  https://doi.org/10.1002/advs.202406218
FASEB J. 2025 Jan 15. 39(1): e70301

Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.

Hanna Englert, Chandini Rangaswamy, Giuliano A Kullik, Mylène Divivier, Josephine Göbel, Irm Hermans-Borgmeyer, Uwe Borgmeyer, Kerri A Mowen, Manu Beerens, Maike Frye, Reiner K Mailer, Mathias Gelderblom, Evi X Stavrou, Roger J S Preston, Stefan W Schneider, Tobias A Fuchs, Thomas Renné.

  Neutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E. coli or the transgenic expression of granulocyte colony-stimulating factor (G-CSF), each induced NET-mediated lethal vascular occlusions in mice with combined genetic deficiency in Dnase1 and Dnase1l3 (D1/D1l3-/-). In accordance with the signaling of toll-like receptors, Myd88/D1/D1l3-/- animals were protected from the formation of lethal intravascular NETs during septic conditions. However, this protection was not observed during neutrophilia. It was unexpected to find that both Gsdmd/D1/D1l3-/- and Pad4/D1/D1l3-/- mice were fully capable of forming NETs upon LPS/E.coli challenge. Sepsis equally triggered a similar inflammatory response in these mice characterized by formation of DNA-rich thrombi, vessel occlusions, and mortality from pulmonary embolism, compared to D1/D1l3-/- mice. Pharmacologic GSDMD inhibitors did not reduce PMA-stimulated NET formation in ex vivo models either. Similarly, neither Pad4 nor GSDMD deficiency affected intravascular occlusive NET formation upon neutrophilia challenge. The magnitude of NET production, multi-organ damage, and lethality were comparable to those observed in challenged control mice. In conclusion, our data indicate that NET formation during experimental sepsis and neutrophilia is regulated by distinct stimulus-dependent pathways that may be independent of canonical PAD4 and GSDMD.

Keywords:  GSDMD; PAD4; immunothrombosis; inflammation; neutrophil extracellular traps; vascular biology

DOI:  https://doi.org/10.1096/fj.202402514R
J Control Release. 2025 Jan 25. pii: S0168-3659(25)00083-5. [Epub ahead of print]

Mannose-modified exosomes loaded with MiR-23b-3p target alveolar macrophages to alleviate acute lung injury in Sepsis.

Jiezhi Lin, Lu Yang, Tianyi Liu, Hui Zhao, Yingying Liu, Futing Shu, Hongchao Huang, Wenzhang Liu, Wei Zhang, Luofeng Jiang, Shichu Xiao, Yongjun Zheng, Zhaofan Xia.

  The anti-inflammatory role of miR-23b-3p (miR-23b) is known in autoimmune diseases like multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. However, its role in sepsis-related acute lung injury (ALI) and its effect on macrophages in ALI remain unexplored. This investigation aimed to evaluate miR-23b's therapeutic potential in macrophages in the context of ALI. The study found reduced miR-23b expression in macrophages within ALI tissue. Intratracheal delivery of miR-23b mimics alleviated ALI by partially inhibiting M1 macrophage activation through the Lpar1-NF-κB pathway. Effective delivery systems are crucial for prolonging miR-23b activity in the lungs, reducing dosage, and minimizing side effects by specifically targeting macrophages. However, current vector systems for nucleic acid delivery, including viral, lipid-based, polymer-based, and peptide-based vectors, face limitations due to eliciting immune responses. Exosomes have garnered significant attention as a leading gene delivery system due to the safety, effectivity and low immunogenicity. We further isolated exosomes from bone marrow-derived mesenchymal stem cells, modified exosomes with mannosylated ligands to enhance the targeted delivery of miR-23b to macrophage. This approach represents a promising novel therapeutic strategy for treating sepsis-induced ALI.

Keywords:  Acute lung injury; Exosomes; Macrophages; MiR-23b-3p; Sepsis

DOI:  https://doi.org/10.1016/j.jconrel.2025.01.073
J Exp Med. 2025 Apr 07. pii: e20241207. [Epub ahead of print]222(4):

Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks.

Immunological Genome Project Consortium

Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.

DOI: https://doi.org/10.1084/jem.20241207