The Journal of Immunology最新文献_第7页

NCG-hIL15 humanized mice - an ideal model for human immune reconstitution of NK cells NCG-hIL15人源化小鼠-人类NK细胞免疫重建的理想模型

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.237.12

S. Chen, Xing Liu, Meirong Wu, Huiyi Wang, Weiwei Yu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Zhiying Li, M. Moore, Jing Zhao, Gao Xiang

{"title":"NCG-hIL15 humanized mice - an ideal model for human immune reconstitution of NK cells","authors":"S. Chen, Xing Liu, Meirong Wu, Huiyi Wang, Weiwei Yu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Zhiying Li, M. Moore, Jing Zhao, Gao Xiang","doi":"10.4049/jimmunol.210.supp.237.12","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.237.12","url":null,"abstract":"\u0000 Immunodeficient NCG mice were unable to reconsituted human NK cells, but after knockin of human IL-15 (hIL-15), the NCG-hIL15 mice could assist the reconstitution of human NK cells. Compared with NCG, the level of hIL-15 was significantly increased in heterozygous and homozygous NCG-hIL15 mice. After transplanting human PBMC (huPBMC-NCG-hIL15) or NK cells into NCG-hIL15 (huNK-NCG-IL15), the level of peripheral blood hCD56+ NK cells in huNK-NCG-hIL15 mice were much higher than that in huPBMC-NCG-hIL15 mice. However, the reconstituted proportion of human CD3+ T cells in huNK-NCG-hIL15 mice was not comparable in huPBMC-NCG-hIL15 mice. The level of NK cell reconstitution is also highly dependent on the donor NK cells. The expression of perforin in the peripheral blood of huNK-NCG-hIL15 mice was significantly higher than that in huPBMC-NCG-hIL15 mice. In vitro functional analysis of NK cells from huPBNK-NCG-hIL15 and huPBMC-NCG-hIL15 showed Granzyme B expression in peripheral blood were comparable and human NK cells purified from splenocytes of huPBNK-NCG-hIL15 mice were cytotoxic upon coculture with Raji cells in the presence of Rituximab. Based on these in vitro data, we established huNK-NCG-hIL15 mice subcutaneously engrafted with Raji cells, and the in vivo efficacy of rituximab was evaluated. Efficacy study data showed that rituximab significantly inhibited the Raji tumor cells growth in huNK-NCG-hIL15 mice. Both huPBMC-NCG-hIL15 and huNK-NCG-hIL15 mouse model can rapidly reconstitute functional human NK cells compared to CD34+ HSC engrafted NCG-hIL15 mice. The development of huNK-NCG-hIL15 is an ideal mouse model to specifically evaluate the anti-tumor efficacy of drugs targeting human NK cells.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"149 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77481129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nonencapsulated Streptococcus pneumoniaeavoid innate immunity clearance through reactive oxygen species resistance 非包裹性肺炎链球菌通过活性氧抵抗避免先天免疫清除

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.82.21

L. McDaniel, C. Thompson, Shelby Holcomb, Lance E. Keller

{"title":"Nonencapsulated Streptococcus pneumoniaeavoid innate immunity clearance through reactive oxygen species resistance","authors":"L. McDaniel, C. Thompson, Shelby Holcomb, Lance E. Keller","doi":"10.4049/jimmunol.210.supp.82.21","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.82.21","url":null,"abstract":"\u0000 Neutrophils provide an important mechanism of clearance for Streptococcus pneumoniae. Therefore, evasion of the innate immune response is essential for pneumococci to cause disease. The pneumococcal capsule is protective against phagocytosis but nonencapsulated Streptococcus pneumoniae (NESp) lack this capsule. Despite the lack of capsule NESp effectively colonize and cause invasive and noninvasive disease. All invasive isolates of NESp express the oligopeptide transporters AliC and AliD, which are required for virulence in multiple animal models. AliC and AliD alter downstream gene expression, and it is hypothesized that one of these regulated genes is responsible for increased immune evasion of NESp. A mutant library of AliC/AliD regulated genes was created and tested for virulence in a Galleria mellonella model of infection. Genes of interest from the in vivo screen were tested for the ability to resist phagocytic killing by neutrophil-like cells. Resistance to killing through reactive oxygen species (ROS) was examined. Of the seven AliC/AliD regulated genes tested, LytFN1 and MgtC mutants were found to have significantly reduced virulence compared to wildtype. A 40% decrease in resistance to phagocytic killing was observed in both mutants, as well as significantly decreased survival during exposure to ROS from growth in 2.5 mM hydrogen peroxide. Expressing AliD in a pneumococcal background that does not natively have the oligopeptide transporter significantly increased virulence and ROS resistance. Regulation of gene expression by AliC and AliD promote pneumococcal survival and virulence by increasing resistance to ROS mediated clearance and partially complements the lack of the opsonophagocytosis resistant capsule.\u0000 Institutional funds","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77609309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Understanding Mechanisms of Adjuvancy in Muscle by mRNA/Lipid Nanoparticles 了解mRNA/脂质纳米颗粒在肌肉中的辅助作用机制

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.253.04

Devdoot Majumdar, W. Dowell, Sylvester Languon, Zachary D. Miller, Jake Dearborn

{"title":"Understanding Mechanisms of Adjuvancy in Muscle by mRNA/Lipid Nanoparticles","authors":"Devdoot Majumdar, W. Dowell, Sylvester Languon, Zachary D. Miller, Jake Dearborn","doi":"10.4049/jimmunol.210.supp.253.04","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.253.04","url":null,"abstract":"\u0000 Vaccines utilizing encapsulated mRNA within lipid nanoparticles (LNPs) have demonstrated unprecedented efficacy in clinical studies of mRNA-1273 and BNT162b2, two prominent vaccines developed against the S protein of SARS-CoV-2. Despite several Phase III trials offering deep clinical intuition about vaccine efficacy, the musculo-immune basis for elicitation of a strong germinal center response from mRNA/LNP vaccine remains unclear. Here, we characterize the trajectory of the immune response to an mRNA lipid nanoparticle vaccine, encapsulated in sm-102 (Moderna). Furthermore, we find that intramuscular administration of empty LNPs elicits a strong neutrophil and dendritic response within 24h. Additionally, we show that skeletal muscle may play a role in the early immune response to mRNA LNPs. Inflammatory LNPs thus contribute to the well-established role of RNA immunogenicity. Using a reporter of transduction, we show that both >10% of muscle-resident myeloid and lymphoid cells are directly transduced with mRNA vaccines, and that these cells play a crucial role in the downstream germinal center response. Transcriptomic measurements of muscle tissue reveal a direct role role of ionizable lipid operating as an adjuvant to induce this response. Using in vitro and molecular tools, these studies advance our understanding of the cellular and molecular basis for LNP-mediated inflammation and adjuvancy underpinning the exceptional clinical efficacy of mRNA/LNP vaccination.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78046325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unraveling myeloid cell-mediated mechanisms of resistance to immune checkpoint blockade in bladder cancer 揭示膀胱癌中骨髓细胞介导的免疫检查点阻断抵抗机制

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.84.15

Michelle A. Tran, A. Farkas, Karen Lee, A. Horowitz, K. Beaumont, R. Sebra, J. Sfakianos, M. Galsky, N. Bhardwaj

{"title":"Unraveling myeloid cell-mediated mechanisms of resistance to immune checkpoint blockade in bladder cancer","authors":"Michelle A. Tran, A. Farkas, Karen Lee, A. Horowitz, K. Beaumont, R. Sebra, J. Sfakianos, M. Galsky, N. Bhardwaj","doi":"10.4049/jimmunol.210.supp.84.15","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.84.15","url":null,"abstract":"\u0000 \u0000 \u0000 Only 15–25% of bladder cancer (BC) patients respond to PD-(L)1 immune checkpoint blockade (ICB) therapy. We previously used pre-treatment tumor to derive an ICB response gene signature that was enriched in adaptive immune genes and an ICB resistance signature enriched in innate immune and inflammatory genes.\u0000 \u0000 \u0000 \u0000 We performed single-cell RNA sequencing (scRNAseq) on 27 bladder tumors and 3 normal-adjacent tissue specimens to resolve these signatures. We profiled tumor macrophages (MΦs) underlying the resistance signature with flow cytometry (FC). To recapitulate them, we used healthy donor blood monocytes differentiated with M-CSF, skewed with predicted ligands, and characterized by FC, RTqPCR, and bulk RNAseq. To examine for peripheral biomarkers, we conducted scRNAseq on paired blood and urine and performed O-Link and ELISA on plasma.\u0000 \u0000 \u0000 \u0000 Our ICB response and resistance signatures were enriched in distinct MΦ subsets: immunostimulatory (is)MΦs and pro-tumorigenic (pt)MΦs, respectively. ptMΦs upregulated SPP1, TREM1, and CLEC5Aand pro-inflammatory and hypoxic programs whereas isMΦs upregulated antigen presentation and complement machinery. ptMΦs were enriched in tumor versus normal tissue. When we tested ptMΦ predicted drivers, IL-1β induced expression of Clec5a and Trem1 protein and transcription of SPP1, TREM1, and CLEC5A. In the first-ever BC urine scRNAseq, we discovered urine contains ptMΦs. Corresponding inflammatory cytokines (IL-1β, IL-6, IL-8) were elevated in advanced patient plasma compared to early stage and healthy donors. In conclusion, we identified pro-inflammatory SPP1+CLEC5A+TREM1+MΦs that may underlie ICB resistance, be targeted via IL-1β and monitored via plasma and urine.\u0000 \u0000 \u0000 \u0000 Supported by grants from NIH (F30 CA275269-01, R01 CA249175-01).\u0000","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"138 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79814503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chemotherapy-Induced Thymic Involution: An Ultrastructural Study 化疗诱导胸腺退化:一项超微结构研究

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.219.14

M. Lagou, Xheni Nishku, Joseph Churaman, L. Cummins, F. Macaluso, G. Karagiannis

{"title":"Chemotherapy-Induced Thymic Involution: An Ultrastructural Study","authors":"M. Lagou, Xheni Nishku, Joseph Churaman, L. Cummins, F. Macaluso, G. Karagiannis","doi":"10.4049/jimmunol.210.supp.219.14","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.219.14","url":null,"abstract":"\u0000 Endogenous thymic repair is quite complex, demanding coordinated thymocyte and thymic stromal responses for T cell development and establishment of central tolerance. While the importance of thymic stroma, notably cortical (cTEC) and medullary (mTEC) thymic epithelial cells, has been shown in gain- and loss-of-function studies, endogenous thymic epithelial repair has never been resolved ultrastructurally. Using Transmission Electron Microscopy (TEM), we analyzed morphometrically thymi in mice receiving Cyclophosphamide (CTX). In vehicle-treated mice, the cortex was populous with thymocytes neighboring cTEC, which extended long cytoplasmic processes into a dendritic meshwork, called “cytoreticulum”. In CTX-treated mice though, thymocytes were scarcely met in the cortex and TEC appeared more circular/ellipsoid. The cytoreticulum was evidently collapsed, increasing total contact surface area among cTEC/mTEC subsets. Despite that thymic macrophages primarily mediate clearance of thymocytes failing positive/negative selection, those in CTX-treated thymi were rich in secondary lysosomes and many were found phagocytosing TEC. The surviving TEC in CTX-treated mice had increased autophagolysosomes per surface area unit of TEC cytoplasm compared to vehicle-treated ones. Analysis via intensity thresholding revealed higher electron density of enclosed particles, consistent with the presence of partly-digested amorphous material, indicating membranous organelle self-digestion (i.e., stress macroautophagy). These data propose an emerging hypothesis that survival of thymic epithelium following cytotoxic insult is mediated via a collective stress response involving macroautophagy activation in TEC.\u0000 Funded by: 1)AAI careers in immunology Fellowship - trainee 2)new investigator's start up funds (PI)","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79919712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SARS-CoV-2 Delta requires human ACE2 but not human TMPRSS2 to infect mice and elicits greater lung injury and adaptive immune response than Omicron in human ACE2 knock-in mice SARS-CoV-2 δ需要人ACE2而不需要人TMPRSS2才能感染小鼠，并且在人ACE2敲入小鼠中引起比Omicron更大的肺损伤和适应性免疫反应

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.75.04

S. Verma, Fernanda Ana-Sosa-Batiz, N. Shafee, Julia Timis, Erin Maule, Robyn Miller, Paolla DA Pinto, Kristen M. Valentine, Chris Conner, Devid Webb, K. Jarnagin, Kenneth Kim, S. Shresta

{"title":"SARS-CoV-2 Delta requires human ACE2 but not human TMPRSS2 to infect mice and elicits greater lung injury and adaptive immune response than Omicron in human ACE2 knock-in mice","authors":"S. Verma, Fernanda Ana-Sosa-Batiz, N. Shafee, Julia Timis, Erin Maule, Robyn Miller, Paolla DA Pinto, Kristen M. Valentine, Chris Conner, Devid Webb, K. Jarnagin, Kenneth Kim, S. Shresta","doi":"10.4049/jimmunol.210.supp.75.04","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.75.04","url":null,"abstract":"\u0000 SARS-CoV-2 pathogenesis remains poorly understood in large part due to lack of knowledge about the mechanisms of entry and behaviors of SARS-CoV-2 variants in vivo. We generated single and double knock-in (KI) mice expressing human ACE2 (hACE2) and/or human TMPRSS2 (hTMPRSS2) under endogenous promoters in place of murine ACE2 (mACE2) and TMPRSS2 on the C57BL/6 and BALAB/c genetic backgrounds to evaluate Delta vs Omicron BA.1 infection, disease, and immune response. Delta replication was observed in lungs of mice expressing hACE2 but not hTMPRSS2 or mACE2 following intranasal inoculation, and similar levels of Delta replication were observed in lungs of hACE2-KI and hACE2xhTMPRSS2-KI mice. Thus, Delta requires hACE2 but not hTMPRSS2 to infect mice. In contrast, BA.1 established similar levels of replication in lungs of single and double KI mice, demonstrating that BA.1 requires neither hACE2 nor hTMPRSS2 to infect mice. Although no significant differences in viral burden were observed in hACE2-KI mice infected with Delta vs BA.1, Delta-infected hACE2-KI mice exhibited increased histopathologic lung injury and higher SARS-CoV-2-specific CD4+ and CD8+ T cell responses (spleen) and anti-SARS-CoV-2 spike IgG titers (serum). Additionally, hACE2-KI mice on the C57BL/6 background showed more severe lung disease and stronger Th1 response than BALB/c. These results associate the severity of lung disease with the magnitude of Th1-dominant immune responses, and set a foundation for dissecting mechanisms of COVID-19 pathogenesis in hACE2-KI mice representing Th1- vs Th2-dominant genetic backgrounds.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80286284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sulfides in the gut mediate protection against gastrointestinal infection via alterations to local immunity and the microbiome 肠道中的硫化物通过改变局部免疫和微生物组介导对胃肠道感染的保护

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.227.07

Victor I Band, A. Stacy, Joanna Chau, Y. Belkaid

{"title":"Sulfides in the gut mediate protection against gastrointestinal infection via alterations to local immunity and the microbiome","authors":"Victor I Band, A. Stacy, Joanna Chau, Y. Belkaid","doi":"10.4049/jimmunol.210.supp.227.07","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.227.07","url":null,"abstract":"\u0000 Sulfide is a gaseous molecule, which has toxic effects at high concentrations yet plays key roles in homeostasis throughout the body. Sulfides are produced endogenously by both host tissues and the bacterial cells of the gut microbiome, which results in the gut containing the highest concentrations of sulfide in the body. We sought to assess the role of the highly abundant sulfide molecule in gut immunity, microbiome homeostasis and resistance to enteric infections. Local sulfides can be depleted by the compound bismuth subsalicylate (BSS), a common anti-diarrheal medication, which acts locally by sequestering sulfides in the gut. Key gut commensals such as Lactobacillusand segmented filamentous bacteria, major mediators of gut immunity and resistance to pathogen colonization, were profoundly depleted following sulfide sequestration. Additionally, we observed significant downstream immune effects, specifically within the local immunity of the small intestine. Depletion of gut sulfides resulted in profound collapse of CD4 T cells, especially among Th1 cells in the lamina propria of the small intestine. Using a mouse model of SalmonellaTyphimurium, mice treated with BSS were extremely susceptible to infection, with a 5-log increase in fecal bacterial load at 24 hours post infection. These data reveal a central role for sulfides in gut homeostasis and prevention of enteric infection. Strategies to manage gut sulfide levels, including diet supplementation and microbiome engineering, could be a possible intervention to promote gut health.\u0000 NIH Office of Dietary Supplements (Research Scholar Grant 2022)","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"160 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79250846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GATA2-TGF-b1 axis regulates human NK cell development GATA2-TGF-b1轴调控人NK细胞发育

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.162.02

Dandan Wang, K. Myers, E. Bresnick, J. Verbsky, M. Thakar, S. Malarkannan

{"title":"GATA2-TGF-b1 axis regulates human NK cell development","authors":"Dandan Wang, K. Myers, E. Bresnick, J. Verbsky, M. Thakar, S. Malarkannan","doi":"10.4049/jimmunol.210.supp.162.02","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.162.02","url":null,"abstract":"\u0000 Natural killer (NK) cells, a subset of innate lymphocytes, produce proinflammatory cytokines and mediate anti-tumor cytotoxicity. GATA2 is a master transcription factor that is essential for the development of erythroid, myeloid, B, and NK cells. Patients with GATA2 haploinsufficiency lack CD56 brightNK cells (immature), with or without a reduction in the number of CD56 dimNK cells (mature). However, how GATA2 functions to establish and maintain genetic networks during the development and function of human NK cells is unknown. Here, we identify a novel GATA2-TGF-b1 axis that regulates NK cell development. We performed single-cell RNA-seq with NK cells from three GATA2 T354Mpatients and found significantly reduced expression of immediate early genes, which indicated that they are functionally-defective. We discovered a reduction in TGF-b1 transcripts and defective expression of TGF-b1 target genes in NK cells from GATA2 T354Mpatients. Using a reporter assay, we determined that GATA2 occupy to TGFB1 promoter, and this association was decreased in GATA2 T354MNK cells. ATAC-seq of GATA2 T354MNK cells indicates significantly altered chromatin accessibility. GATA2 CUT&Tag-seq validated that it occupies the TGFB1 promoter region, which correlated with activation of the TGFB1 locus in human NK cells. In summary, we define a mechanism by which GATA2 controls TGF-b1 production in human NK cells and thereby regulating their development. These findings provide vital clues for developmental and functional defects of NK cells in GATA2 T354Mpatients.\u0000 ASH Graduate Hematology Award (D.W.); GIRT Award from MCW-C4I (D.W.); NIH R01 AI102893 and NCI R01 CA179363 (S.M.); HRHM Program of MACC Fund (S.M.), Nicholas Family Foundation (S.M.); Gardetto Family (S.M.); MCW-Cancer Center-Large Seed Grant (S.M. and M.S.T.); MACC Fund (S.M.); Ann’s Hope Mela- noma Foundation (S.M.); and Advancing Healthier Wisconsin (S.M.)","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79441792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hepatic regulatory T-cells promote colorectal liver metastasis in NASH 肝调节性t细胞促进NASH患者结肠肝转移

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.63.20

Jiannan Hu, Han Wang, Hongji Zhang, Jinghua Ren, Xiang Cheng, Yonghong Yao, A. Tsung, Hai Huang

{"title":"Hepatic regulatory T-cells promote colorectal liver metastasis in NASH","authors":"Jiannan Hu, Han Wang, Hongji Zhang, Jinghua Ren, Xiang Cheng, Yonghong Yao, A. Tsung, Hai Huang","doi":"10.4049/jimmunol.210.supp.63.20","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.63.20","url":null,"abstract":"\u0000 \u0000 \u0000 Non-alcoholic steatohepatitis (NASH), a progressive inflammatory form of NAFLD, underlies an extremely versatile and dynamic inflammatory microenvironment along with aberrant metabolism and ongoing liver regeneration. Regulatory T cells (Tregs), as essential immune regulatory cells, are critical for the inhibition of tumor-promoting inflammation and cancer cell escape. Our recent study found that Tregs were selectively increased in both mouse models and patients with NAFLD, which promotes us to study the role of Tregs in NASH-HCC. However, the role of Tregs in the development of hepatic metastasis in NASH liver remains unknown.\u0000 \u0000 \u0000 \u0000 A Western diet mouse model and the STAM mouse model were utilized for NASH development. MC38 murine colorectal tumor cells were injected via portal vein at 12 weeks of feeding or orthotopically injected into cecum subserosa. Tumor development will be determined 3 or 4 weeks after injection. Depletion of Tregs by FoxP3-DTR mice or CD25 antibody treatment. Transcriptomic profiling of leucocytes in hepatic immune microenvironment was determined by scRNA-seq.\u0000 \u0000 \u0000 \u0000 There is a positive correlation between increased Tregs and hepatic tumor growth in NASH liver. Depleting Tregs inhibits the development of hepatic metastasis in NASH liver compared with control liver. NASH development led to a significant transcriptomic shift in hepatic immune cells, such as Kupffer cells, Tregs and MDSCs. Blocking the interaction of Tregs and PMN-MDSCs in the TME prevents tumor growth in the NASH liver.\u0000 \u0000 \u0000 \u0000 Tregs can suppress immunosurveillance in the premalignant stages of NASH. Therapies targeting Tregs could offer a potential strategy for preventing hepatic metastasis in patients with NASH.\u0000 \u0000 \u0000 \u0000 RO1GM137203\u0000","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"123 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79476223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PD-L1 blockade enhances brain resident memory T cell function and stimulates brain to lymph node crosstalk PD-L1阻断可增强脑常驻记忆T细胞功能，刺激脑淋巴串扰

The Journal of Immunology Pub Date : 2023-05-01 DOI: 10.4049/jimmunol.210.supp.59.20

Shawn C. Musial, Sierra A. Kleist, Tyler G. Searles, Hanna N. Degefu, Jordan F. Isaacs, Alexander G. J. Skorput, Pamela C. Rosato

{"title":"PD-L1 blockade enhances brain resident memory T cell function and stimulates brain to lymph node crosstalk","authors":"Shawn C. Musial, Sierra A. Kleist, Tyler G. Searles, Hanna N. Degefu, Jordan F. Isaacs, Alexander G. J. Skorput, Pamela C. Rosato","doi":"10.4049/jimmunol.210.supp.59.20","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.59.20","url":null,"abstract":"\u0000 Resident memory T cells (T RM) are a unique subset of memory T cells that persist within non-lymphoid tissues. Previous studies have identified T RMwithin the brain (bT RM) after peripheral infection and vaccination in mice, with more recent appreciation in human brain tissue. While bT RMare important for protection of the CNS against reinfection, their heterogeneity at the single cell level and overall involvement in shaping the neuroimmune landscape remains unknown. Here, we defined viral-specific bT RMheterogeneity by single cell RNA sequencing and identified unique subsets dependent on local antigen encounter. These data also confirmed previous findings that bT RMexpress markers associated with T cell exhaustion, such as PD-1. Despite this, intracranial delivery of cognate viral peptide led to robust bT RMreactivation and initiated a cascade of immune activation and accumulation within the brain, including rapid activation of microglia, NK cells and T cells, DC maturation, and infiltration of macrophages and monocyte derived DCs. In the presence of PD-L1 blockade, despite observing higher effector molecule production from reactivated bT RM, we found no apparent difference in downstream immune activation in the brain. Interestingly, however, we found a significant increase in DC and B cell maturation in the CNS draining deep cervical lymph nodes (dcLN) only in the presence of PD-L1 blockade. These data indicate a potential unique crosstalk between bT RMand APCs in the dcLN normally suppressed by PD-1/PD-L1 signaling. These studies provide insight into brain T RMfunctions and potential mechanisms for strengthening immune activation that can guide immunotherapies for immunologically cold brain tumors.\u0000 Supported by grants from the NIH (K22AI148508-02, T32 AI007363)","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81415575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0