Abstract
Although inflammatory complications are common in preterm infants, the effects of these conditions on neonatal immune development remain poorly defined. We therefore investigated whether severe bronchopulmonary dysplasia (BPD) and systemic infection, 2 major complications of prematurity, produce distinct immune signatures and change immune composition over time. We performed longitudinal high-dimensional immune profiling of residual whole blood from 38 preterm infants sampled every 2 weeks, along with 10 term infants at birth. Preterm infants with severe BPD showed a progressive increase in Th17-polarized CD4+ T cells, neutrophils, and Th17-related cytokines compared with age-matched infants with moderate BPD. In contrast, some preterm infants with systemic bacterial or viral infections mounted exceptionally robust CD8+, CD4+, and γδ T cell responses, with oligoclonal expansion, terminal differentiation, and coordinated plasma cytokine shifts that persisted well beyond resolution of infection. These findings demonstrate that different preterm comorbidities imprint the neonatal immune system in divergent ways. Thus, comprehensive and longitudinal immune profiling may not only identify connections between clinical inflammatory complications and underlying immune pathways but also reveal potential targets for intervention.
Authors
Benjamin A. Fensterheim, Michelle L. McKeague, Divij Mathew, Shwetank, Ajinkya Pattekar, Matthew Lee, Zahabia Rangwala, Sean Nasta, Macy C. Kee, Cynthia Clendenin, Zachary Martinez, Caroline Diorio, Allison R. Greenplate, Krithika Lingappan, E. John Wherry
Loss of tumor-infiltrating lymphocytes and poor response to immunotherapy in IDH GOF mutant melanoma
Abstract
Recent innovations in melanoma treatment with immune checkpoint blockade (ICB) have improved overall outcomes for patients; however, over 50% of patients still develop resistance to treatment. These patients either have intrinsic resistance and never respond to therapy or develop acquired resistance months or years into treatment. The mechanisms underlying ICB resistance remain poorly understood. Our data show that patients with isocitrate dehydrogenase gain-of-function (IDH GOF) mutant melanoma have a worse response to anti-PD1 immunotherapy. IDH mutations have been found to be oncogenic and associated with differential methylation in multiple cancers but are not yet characterized in human melanoma. Here, we investigate the clinical, immune, and transcriptional phenotypes of IDH GOF melanomas through analyses of clinical response, single-cell RNA-seq, bulk RNA-seq, and DNA methylation data. Single-cell data analysis showed decreased immune infiltrate and activity in the IDH GOF tumors. Bulk sequencing data demonstrated the association among IDH mutation, immune exclusion, and disruptions in global DNA methylation. The melanoma-derived genomic data presented support previously described resistance mechanisms of IDH mutation in other cancer types and is the first demonstration to our knowledge of the role of IDH GOF in the human melanoma tumor microenvironment.
Authors
Emma Specht, Lakshmi Pakanati, Meng-Ju Wu, Russell W. Jenkins, Derek N. Effiom, Nabeel Bardeesy, Bradley E. Bernstein, Moshe Sade-Feldman, Christine G. Lian, Genevieve M. Boland, Elena Torlai Triglia, Sonia Cohen
Abstract
Interscapular brown adipose tissue (BAT), one of the most vascularized tissues in the body, exemplifies the intricate crosstalk between the vascular system and adipocytes. BAT is known to secrete abundant exosomes into circulation, and exosomes are known to play a key role in vascular remodeling and cell migration. However, whether BAT-derived exosomes (BATexos) modulate peripheral vasculature remains unclear. Here, we report that BATexos promoted peripheral angiogenesis and vascular repair. Among their cargo, miR-378a-3p was highly enriched and identified as a key mediator of endothelial angiogenic function. The overexpression of miR-378a-3p in endothelial cells substantially promoted cell migration and tube formation. Conversely, inhibition of exosome secretion from BAT impaired vascular repair and delayed wound healing. Mechanistically, miR-378a-3p directly targeted the phosphatase and tensin homolog (Pten), thereby activating the PI3K/AKT signaling pathway. Liposomes encapsulating miR-378 mimics promoted angiogenesis and accelerated wound healing in a diabetic mouse model. Collectively, this study uncovers BAT-derived miR-378a-3p as a key regulator of vessel regeneration and tissue repair after injury, offering therapeutic potential for treating vascular complications in metabolic disease.
Authors
Hongyan Deng, Yuyu Xie, Jiadai Liu, Jing Ge, Qianqian Kang, Rui He, Zhihan Wang, Xuemin Peng, Zengzhe Zhu, Wenshe Wang, Yulian Liu, Ronghui Gao, Ruping Pan, Min Yang, Yong Chen
Abstract
Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA), yet its mechanism remains unclear. RA synovium exhibits metabolic shift, characterized by upregulated glycolysis and enhanced lactate production. In this study, we elucidated the mechanism underlying the roles of lactate metabolism and protein lactylation in RA pathology. In patients with RA, both lactate production and protein lactylation were elevated and showed a positive correlation with clinical disease activity. These changes were further implicated in driving synovial proliferation. Among the lactylated proteins, Cysteine-rich intestinal protein 1 (CRIP1) exhibited a marked increase in modification and played a central role in promoting synovial proliferation. Mechanistically, CRIP1 underwent MOF-mediated lactylation in RA synovial fibroblasts. Lactylated CRIP1 hijacked the cell-cycle regulator p21, disrupting its interaction with cyclin-dependent kinase 2 (CDK2), thereby facilitating the G1/S phase transition. Functionally, AAV-mediated delivery of a lactylation-deficient CRIP1 K49R significantly reduced synovial proliferation compared with WT CRIP1. Peptide-based interventions targeting CRIP1 K49 lactylation effectively inhibited synovial hyperplasia and disease severity in both Collagen II–induced arthritis (CIA) and humanized NSG chimeric models. Collectively, CRIP1 protein lactylation drives synovial proliferation in RA by hijacking p21 from CDK2, thereby facilitating cell cycle progression. Targeting this pathway may serve as a promising strategy for RA.
Authors
Meican Ma, Yu Zhou, Qianlin Li, Zhao Wang, Shangqi Guan, Xiaoxue Wang, Han Zhao, Zhenke Wen, Ting Liu, Fenghong Yuan
Abstract
Human CD4+ T cells utilize nutrients, including lipids, to support their activation and polarization. Considering the pivotal role of lipoproteins in lipid transport, we reasoned that lipoprotein uptake and processing could effect CD4+ T cell function. Here, we demonstrate that activation of human CD4+ T cells induced expression of LDL receptor (LDLR) to facilitate LDLR-mediated endocytosis of LDL. Degradation of surface LDLR on CD4+ T cells with PCSK9 hampered activation and proliferation of the cells. Lipoprotein deprivation or blocking of lysosomal cholesterol egress impaired activation of mechanistic target of rapamycin complex 1 (mTORC1), affecting CD4+ T cell activation and proliferation. Furthermore, lipoprotein deprivation of cultured primary CD4+ T cells lead to reduced expression of c-MAF and FOXP3, key transcription factors for IL-10, accompanied by reduced IL-10 secretion. The pivotal role of LDLR-mediated lipoprotein uptake for mTORC1 activity, c-MAF and FOXP3 expression, and IL-10 secretion was confirmed using LDLR-dysfunctional CD4+ T cells from patients with homozygous familial hypercholesterolemia. Our study offers valuable insights into the lipoprotein metabolism of human CD4+ T cells and their reliance on the LDLR pathway for activation and polarization, a feature that may be leveraged to modulate CD4+ T cell function.
Authors
Angela Markovska, Niels S. van Heusden, Dagmar Duijzer, Alejandra Bodelón, Greta Rogani, Enric Mocholi, Edwin C.A. Stigter, Can Gulersonmez, Sander Kooijman, Leonie Van der Zee, Monique T. Mulder, Jeanine E. Roeters van Lennep, Patrick C.N. Rensen, Jorg van Loosdregt, Sebastiaan J. Vastert, Noam Zelcer, Marianne Boes, Henk S. Schipper
Abstract
It remains unclear why vaccines targeting prominent microbial virulence factors often fail in clinical trials. Because microbial virulence depends on interaction with the host immune system, we investigated how changes in host immune function alter vaccine efficacy. Using a vaccine against Staphylococcus aureus α-toxin (Hla), which targets host metalloprotease ADAM10 on myeloid cells, we show that Hla virulence is reduced in aged mice due to diminished ADAM10 activity and impaired myeloid cell function. Depletion of myeloid cells with cyclophosphamide in young mice similarly reduced toxin virulence. Immunization against Hla conferred strong protection against S. aureus infection in young but not aged mice. These findings indicate that pathogenic functions of microbial factors characterized in immunocompetent young animals may not predict virulence or vaccine efficacy in immunocompromised hosts. These findings underscore the need to account for host immune status in the development and evaluation of vaccines targeting microbial virulence factors.
Authors
Xin Du, Ching Wen Tseng, Elisabet Bjånes, Hunter Gage, Jaclyn Swan, Chih-Ming Tsai, Irshad A. Hajam, Cesia Gonzalez, Brian Lin, Victor Nizet, George Y. Liu
Abstract
Central insulin action in the brain is thought to contribute to metabolic regulation, but the specific hypothalamic nuclei affected in type 2 diabetes (T2D) remain poorly characterized. We performed high-resolution functional MRI (fMRI) during intranasal insulin administration to assess nucleus-level hypothalamic responses in 21 Japanese men with T2D and 20 individuals acting as healthy controls. In controls, insulin rapidly suppressed fMRI signals within 5 minutes in the posterior hypothalamic nucleus; this early suppression was not observed in T2D, indicating impaired hypothalamic insulin responsiveness. In an independent older cohort, structural MRI further revealed decreased gray matter volume in the corresponding posterior hypothalamus in participants with diabetes. These converging functional and structural findings implicate the posterior hypothalamus as a candidate locus associated with brain insulin resistance in T2D, warranting longitudinal and interventional validation.
Authors
Hideyoshi Kaga, Akitoshi Ogawa, Takahiro Osada, Mai Kiya, Satoshi Oka, Yusuke Adachi, Mengping Yu, Shota Sakamoto, Saori Kakehi, Toshiki Kogai, Tsubasa Tajima, Hitoshi Naito, Naoaki Ito, Satoshi Kadowaki, Yuya Nishida, Ryuzo Kawamori, Seiki Konishi, Hirotaka Watada, Yoshifumi Tamura
Abstract
Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined, and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza, and SARS-CoV-2–driven pneumonia. Our analysis revealed highly pneumonia type–specific proteomic signatures, including COVID-19–specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V–domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry–driven autoantibody profiling in 2 independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.
Authors
Anna Semenova, Taylor A. Poor, Johannes B. Müller-Reif, Sai Rama Sridatta Prakki, Phillip Geyer, Martin Mück-Häusl, Rogan A. Grant, Luke Rasmussen, Lesca M. Holdt, Daniel Teupser, Matthias Mann, Ali Ö. Yildirim, Richard G. Wunderink, Alexander V. Misharin, Ben D. Singer, G.R. Scott Budinger, Theodore S. Kapellos, Herbert B. Schiller
Abstract
Tumor cells are constantly confronted with nutrient deprivation; however, the effect of serum starvation on the remodeling of endosomal compartments and extracellular vesicles (EVs) in tumor cells remains unclear. Here, we found that serum starvation pronouncedly promotes multivesicular body (MVB) biogenesis, EV formation, and cargo selection. Specifically, by generating a constitutively active Rab5Q79L mutant to induce the enlargement of MVB, we revealed for the first time to our knowledge that ANXA3 is sorted into intraluminal vesicles (ILVs) of MVB. Mechanistically, we confirmed that serum starvation regulates the endosomal sorting complex required for transport–associated (ESCRT-associated) protein ALG-2 interacting protein X (ALIX), which recruits ESCRT-III to MVB and binds to annexin A3 (ANXA3) to mediate its sorting into ILVs of MVB. Our study highlights that serum starvation promotes an ALIX-dependent ESCRT-III recruitment pathway, which loads protumor ANXA3 cargo to exert a profound effect on tumor progression.
Authors
Xueqiang Peng, Jiaxing Liu, Guolong Zeng, Yafei Xiao, Zhixiong Hao, Guangpeng He, Hongyuan Jin, Yu Gao, Shilei Tang, Shibo Wei, Yan Li, Yifan Yu, Liang Yang, Hangyu Li
Abstract
Stem cell–derived β cells offer a promising approach for type 1 diabetes (T1D) treatment. However, the processes of graft infiltration and rejection by immune cells remain poorly understood in humans. In this study, autologous or allogeneic stem cell–derived islets (SC-islets) were transplanted in human immune system mice and analyzed 14 to 18 weeks later. Imaging mass cytometry revealed unique characteristics of SC-islet grafts, including a high percentage of glucagon+ cells and the presence of cysts and CD57+ enterochromaffin cells, features not typically observed in endogenous or transplanted allogeneic primary pancreatic islets. Allogeneic SC-islet grafts exhibited heavy immune infiltration, cell proliferation, and pro-fibrotic processes, whereas autologous grafts showed minimal infiltration and little fibrosis. In some mice, autologous T cells expressing islet antigen-reactive (IAR) T cell receptors (TCRs) were adoptively transferred. Three weeks after transfer, autologous grafts injected with IAR-TCR+ T cells showed negligible immune infiltration, even though IAR-TCR+ T cells were detected in the spleen. Under the conditions tested, human SC-islet grafts were not rejected by an autologous immune system, even in the presence of autoreactive T cells, pointing to several limitations that remain to be addressed for a model of spontaneous autologous SC-islet infiltration and destruction.
Authors
Camillo Bechi Genzano, Giorgia Zanetti, Qian Du, Daniel Traum, Deeksha Lahori, Grant M. Downes, Sakshi A. Bhatele, Xiaolan Ding, Kyle D. Apley, Rebuma Firdessa Fite, Matthew Ishahak, Enrique Eduardo Sanchez-Castro, Jeffrey R. Millman, Yiming Luo, Klaus H. Kaestner, Cory Berkland, Dieter Egli, Megan Sykes, Remi J. Creusot
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