The Journal of Immunology最新文献

{"title":"The impact of the complement receptors C3aR1 and C5aR1 on the progression of melanoma","authors":"S. Oncul, M. Cho, Hani Lee, Wendolyn Carlos-Alcalde, Shailbala Singh, C. Yee, V. Afshar-Kharghan","doi":"10.4049/jimmunol.210.supp.89.09","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.89.09","url":null,"abstract":"\u0000 Melanoma is an aggressive skin cancer that develops from the malignant transformation of pigment-producing skin cells, melanocytes. The incidence of cutaneous melanoma is remarkably high, with an estimated number of new cases in the United States in 2022 close to 100,000 patients. Several previous reports pointed out the effect of the complement system in the progression of melanoma, although the precise mechanism is largely unknown. The complement system is a crucial component of innate immunity, and it also has a significant role in adaptive immunity regulating the function of immune cells. The complement receptors C3aR1 and C5aR1 are present on the surface of various immune cells. Anaphylatoxins (C3a and C5a) generated by complement activation bind to their respective receptors, C3aR1 and C5aR1, suppress the antitumor function of immune cells and promote migration and activity of immunosuppressive cells in the tumor microenvironment. Hence, C3aR1 and C5aR1 act as immune checkpoint receptors. To identify the precise role of the complement receptors in melanoma, we challenged C3 −/−, C3aR1 −/−, and C5aR1 −/−mice with the B16F10 murine melanoma cells. We showed that the deficiency of these molecules substantially delayed tumor growth and promoted an antitumorigenic immune response. The results of this study indicate the distinct role of complement receptor signaling on melanoma growth and suggest a novel immunotherapeutic approach.\u0000 Developmental Research Program Award from the MD Anderson Melanoma SPORE (P50CA221703-04)","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81115716","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}

{"title":"Characterization of the cell-mediated immune response to the NIH tetravalent dengue vaccine in an endemic population","authors":"Jessica Torrey, Iqra Nadeem, Lauren K Gray, Nazinin Omidi, S. Fernandez, S. Whitehead, J. Currier, H. Friberg","doi":"10.4049/jimmunol.210.supp.235.29","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.235.29","url":null,"abstract":"\u0000 Dengue is now endemic in more than 100 countries, with Southeast Asian and Pacific Island regions being the most seriously affected. The Department of Defense has long recognized the threat of dengue and has made great contributions to understanding it. The ideal dengue vaccine will provide long-lasting protection against all four serotypes of dengue virus (DENV1-4) and will be effective in both endemic and non-endemic populations. Several tetravalent dengue vaccines are either licensed or in advanced stages of clinical development, including the live attenuated vaccine candidate developed by the NIH. The purpose of this study is to characterize the cellular immune responses to the NIH vaccine, with particular attention to the activation and memory profiles of DENV-specific T and B cell populations. Our hypothesis is that the NIH vaccine induces a durable and tetravalent DENV-specific adaptive immune response, which varies in its magnitude and phenotype over time (3 years post-vaccination) and across age strata. To assess the magnitude, breadth, and evolution of DENV-specific T and B cells following vaccination, we use a suite of different assays, including IFNγ ELISpot, memory B cell fluorospot, and flow cytometry-based assays. This study evaluates the ability of the NIH vaccine to induce durable and balanced immune responses to all four DENV serotypes, and how that compares to naturally acquired immunity.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"23 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":"85382810","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}

{"title":"Modified Immune Cell (MIC) Therapy disrupts Tertiary Lymphoid Structures in Murine Lupus Nephritis","authors":"G. Ponath, C. Speer, Iris Arnold, A. Hidmark, Lei Wang, C. Kleist, A. Schmitt, V. Daniel, G. Opelz, P. Terness, M. Schmitt, M. Zeier, C. Morath, M. Schaier","doi":"10.4049/jimmunol.210.supp.238.14","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.238.14","url":null,"abstract":"\u0000 Induction of tolerance can be achieved with Modified Immune Cells (MIC) by infusion of mononuclear cells challenged with mitomycin C (MMC). Although MIC treatment has been successful in several animal models for autoimmunity and in clinical studies of solid organ transplantation, the mechanism of immunosuppression is not fully elucidated.\u0000 In lupus nephritis, the glomerular deposition of immune complexes is associated with accumulating immune cells in the kidney. The infiltrating immune cells frequently establish tertiary lymphoid structures (TLS) supporting adaptive autoimmune responses toward locally displayed antigens.\u0000 Since TLS display a high persistence to peripheral B cell depletion, the destruction of TLS presents an essential treatment goal in lupus nephritis. In this study, we used lupus nephritis prone NZB/W F1 mice to show the destruction of TLS in the kidney after MIC treatment.\u0000 Independent of treatment, >86% of animals displayed dense lymphocytic aggregates proximal to the pelvic wall of the medulla and the arcuate arteries within the cortex of kidneys. Cell type composition of TLS changed drastically after MIC treatment leading to diminished B-cells, a decreased B-cell/T-cell ratio, and a T cell dominated phenotype. Furthermore, a loss of organization of the TLS was observed after MIC treatment. The strict separation of B-cell and T-cell areas was abrogated, and germinal centers were disintegrated. However, regulatory T-cells remained unchanged indicative of a B-cell centric treatment mechanism.\u0000 Our data provides a putative in vivomechanism how MIC treatment inhibits progression of active lupus nephritis by the destruction of tertiary lymphoid structures within the kidney.\u0000 Commercial Support - TolerogenixX GmbH","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85427092","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}

{"title":"Pneumoviruses can impair the central nervous system by different mechanisms","authors":"A. Kalergis, Karen Bohmwald, C. A. Andrade","doi":"10.4049/jimmunol.210.supp.236.22","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.236.22","url":null,"abstract":"\u0000 Pneumoviruses such as the respiratory syncytial virus (hRSV) and the human metapneumovirus (hMPV) are the leading cause of acute lower tract respiratory infection, mainly in infants, elderly and immunocompromised individuals, causing high morbidity and mortality rates. However, these viruses can cause neurological alterations, such as encephalitis and encephalopathy. Viral RNA and pro-inflammatory molecules have been found in patients with neurological signs, supporting the notion of neuroinvasion and/or neuroinflammation caused by hRSV and hMPV. Therefore, this work seeks to evaluate the effects of these viruses on the brain. Accordingly, mice were infected with either hRSV or hMPV or treated with non-infectious controls (mock). Despite detecting viral load in the lungs of hMPV-infected mice, no viral load was detected in their brains, as it was shown for hRSV. However, pro-inflammatory cytokines such as IL-6 and IFN-g were increased only in the sera of hMPV-infected mice. Also, we observed differential patterns in the increase of cytokines in the brain of hRSV or hMPV-infected mice, including IL-6, TNF-a, and IL-4. Moreover, increased blood-brain barrier permeability was observed in mice infected with both viruses. Additionally, after several weeks post-infection, a Marble Burying (MB) test was performed, and we observed an impaired cognitive performance in mice infected with both viruses. All these results suggest that infection with these pneumoviruses can cause long-term behavioral impairment in mice. Our work provides new insight into the effect of hRSV and hMPV on the central nervous system and underscores the need to further understand how respiratory virus can damage brain function in humans.\u0000 This work was supported by ANID/FONDECYT grants #11221280; #1190830, ANID scholarship # 21210662, the Millennium Institute on Immunology and Immunotherapy ACE 210015, ICN09_016 / ICN 2021_045; former P09/016-F.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85429470","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}

{"title":"Chlamydia muridarumrecombinant MOMP nanovaccine induces cross-reactive antibodies against Chlamydia trachomatishuman serovars","authors":"Rajnish Sahu, Aguy Clemence Nguiakam Sipowe, Vanella Tadjuidje, W. Geisler, B. Van Der Pol, V. Dennis","doi":"10.4049/jimmunol.210.supp.141.12","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.141.12","url":null,"abstract":"\u0000 Chlamydia trachomatis (CT), caused by various serovars, remains the leading sexually transmitted bacterial infection worldwide. An efficient delivery system is critical to developing whole or subunit vaccines against CT, and some vaccine developmental efforts are targeting biodegradable nanoparticles-based vaccines with encapsulated antigens. We developed a nanovaccine employing the recombinant major outer membrane protein (rMOMP) of C. muridarum (Cm) encapsulated in poly(lactic acid-co-glycolic acid) 85/15 (PLGA-rMOMP). We previously compared the humoral responses of two priming routes, subcutaneous (SC) or intramuscular (IM-p), followed by two SC-boosts to evaluate rMOMP-specific serum antibodies [IgG2a, IgG2b and IgG1] produced by PLGA-rMOMP immunization of female BALB/c mice. Here we used an elementary body (EB)-specific ELISA to investigate the ability of systemic antibodies produced in immunized mice to recognize Cm and to cross-recognize human CT-serovars D, F and J. Serum from mice inoculated with PBS encapsulated PLGA served as negative control. We observed high recognition of Cm specific total IgG (8-fold) and isotypes IgG2a (8-fold), IgG2b (32-fold), IgG1 (8-fold) by SC in comparison to IM-p immunizations. We also observed IgG antibodies recognizing CT-serovars D, F and J from mice immunized via both routes. Evaluation of the Th1 (IgG2a, IgG2b)/Th2 (IgG1) antibody titer ratios revealed that immunization via the SC route induced predominantly Th1 antibodies recognizing both Cm and human CT-serovars. Our data show that mice immunized with PLGA-rMOMP produced high levels of systemic antibodies recognizing Cm, but more importantly, there was a robust serological cross-recognition of the human CT-serovars.\u0000 This research was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number NIH-R21AI111159, NIH-NIGMS-RISE (1R25GM106995-01) and the National Science Foundation (NSF)-CREST (HRD-1241701) and NSF-HBCU-RISE (HRD-1646729) grants.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85455954","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}

{"title":"Glucocorticoids regulate the human non-coding genome","authors":"Robert Ernest Kwiat, T. Tran, Qilin Cao, M. Gadkari, D. Randazzo, L. M. Franco","doi":"10.4049/jimmunol.210.supp.148.24","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.148.24","url":null,"abstract":"\u0000 Glucocorticoids (GCs) are the most commonly used anti-inflammatory and immunosuppressive drugs. However, most of the work on this class of drugs has focused on their relationship to the coding genome. It has been demonstrated in recent years that non-coding genes can play important biological roles. Thus, we performed total RNA-seq and small-RNA-seq in 9 primary human cell types: B cells, CD4+ T cells, monocytes, neutrophils, endothelial cells, fibroblasts, myoblasts, osteoblasts, and preadipocytes, treated in vitro with the GC methylprednisolone. We found that the response of lncRNA genes to GCs appears to be strong and cell type-dependent, with hematopoietic cells being more responsive to GCs than non-hematopoietic cells. Among GC-responsive lncRNAs, the intergenic and RNA host subtypes are overrepresented, while antisense lncRNAs are underrepresented. GC regulation of miRNAs appears to be limited to those that are part of a larger transcript. We generated a global map of GC-responsive lncRNAs and microRNAs in the 9 cell types, and an interactive web application to allow exploration of our results. We identified the lncRNA WAKMAR2 as a GC-induced gene that may play a role in GC action in CD4+ T cells and monocytes. WAKMAR2 has been shown to influence the expression of inflammatory cytokines in non-hematopoietic cells. Single-molecule RNA FISH revealed that, in human monocyte-derived macrophages, WAKMAR2 transcripts are primarily cytoplasmic. Ongoing work is aimed at determining whether WAKMAR2 is in fact a GC-induced negative regulator of inflammatory responses in human primary cells.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85530896","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}

{"title":"Candida albicanspathogenesis in the context of mucosal type II interferonopathy","authors":"Ashira Lubkin, V. Oikonomou, Nicolas Millet, M. Swidergall, M. Lionakis","doi":"10.4049/jimmunol.210.supp.82.13","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.82.13","url":null,"abstract":"\u0000 Interferon-gamma (IFNγ) is a powerful cytokine that is crucial for adequate host defense. However, unchecked IFNγ can cause autoimmunity in several organs and can be directly toxic to host cells. Indeed, excessive IFNγ, or type II interferonopathy, occurs in several diverse disease states, including STAT1 gain-of-function mutations, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), Downs syndrome, and AIDS. We have recently shown that in APECED, which is caused by deficiency of autoimmune regulator (AIRE), excessive IFNγ leads to greater susceptibility to oral Candida albicans infection. C. albicans is both a normal member of the human microbiome and the most common human fungal pathogen. The ability of C. albicans to morph between commensal and pathogenic states is tied to its complex transcriptional regulation of virulence traits in response to environmental cues. Thus, we hypothesize that excessive IFNγ in the oral mucosa leads C. albicans to transition to a more virulent state. We are using transcriptomics to define the response of C. albicans to excess IFNγ. Further, we have found that during infection of oral epithelial cells, C. albicans becomes more invasive in the presence of IFNγ. Thus, we are also using metabolomics to investigate soluble mediators released by these cells in response to IFNγ. These experiments will shed light on C. albicans virulence regulation in response to autoinflammatory conditions. Further, this study will provide new insights into the dualistic nature of IFNγ — providing protection against many pathogens, while facilitating disease from a specific pathogen.\u0000 This work was supported by the Division of Intramural Research of the NIAID (ZIA AI001175).","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"228 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85565254","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}

{"title":"Ablation of PD-1 Reduces the Stability and Lipid Metabolism of Regulatory T Cells in the Tumor Microenvironment","authors":"Myeong Joon Kim, K. Kim, H. Park, Gil-Ran Kim, Kyeong Hee Hong, J. Oh, Jimin Son, D. Park, Dahae Kim, Je-Min Choi, Insuk Lee, S. Ha","doi":"10.4049/jimmunol.210.supp.157.02","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.157.02","url":null,"abstract":"\u0000 Regulatory T cells (T regcells) are responsible for immune homeostasis and highly express PD-1 in the tumor microenvironment (TME). However, the role of PD-1 in tumor-infiltrating (TI) T regcells remains controversial. Indeed, PD-1 expression in T regcells was even higher than in CD8 +T cells and conventional CD4 +T cells. Here, we identified that conditional deletion of PD-1 in T regcells delayed tumor growth by reducing TI T regcell pool and amplifying the functionality of TI CD8 +and CD4 +T cells. In Pdcd1 fl/flFoxp3 eGFP-Cre-ERT2(+/−)mice, in which both PD-1 WTand PD-1 KOT regcells coexisted, TI PD-1 KOT regcells exhibited the impaired proliferative and suppressive capacity compared to TI PD-1 WTT regcells. Additionally, exT regcells, which lost their Foxp3 expression, were more abundant in PD-1 KOT regcells than PD-1 WTT regcells. In TC-1 lung cancer, PD-1 antibody therapy was effective in reducing TI T regcell pool. Single-cell analysis identified that PD-1 signaling promoted various pathways related to lipid metabolism, proliferation, and suppression in TI T regcells. Single-cell TCR sequencing revealed that the clonal expansion of TI T regcells was enriched in PD-1 WTT regcells compared to PD-1 KOT regcells. We also showed that conditional deletion of PD-1 in T regcells reduced lipid uptake and mitochondrial mass of T regcells in TME. These results suggest that PD-1 ablation or blockade can enhance antitumor immunity by exacerbating T regcell stability and metabolic fitness in the TME.\u0000 This study was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (2017R1A5A1014560, 2019M3A9B6065221 to S-.J.H.; 2018R1A5A2025079, 2019M3A9B6065192 to I.L.). This study was also supported by the Korean Health Technology R&D Project (HV20C0144, HN21C1410 to S-.J.H.) through the Korean Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85779075","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}

{"title":"Dynamics of lymphoid-mammary epithelial cell interaction during pregnancy and lactation","authors":"Daniel Yong, Dan Corral, Y. Belkaid","doi":"10.4049/jimmunol.210.supp.150.16","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.150.16","url":null,"abstract":"\u0000 Breast milk has been shown to play a key role in the transfer of immunity from mother to offspring. Antibodies and lymphoid cells can be passed through breast milk and impact offspring immunity. However, the role of these lymphoid cells in lactation and in the control of offspring immunity remains unclear. We observed that the lymphoid cells present in the breast milk are distinct from those found in the blood. Compared to the blood, breast milk T cells are enriched in a T-bet +unconventional population. Imaging analysis revealed that these T-bet +cells gradually accumulate in the mammary gland during pregnancy and are specifically localized around and inside the mammary epithelium. We will utilize confocal and intravital imaging of the mammary gland in virgin, pregnant, and lactating mice to characterize the dynamics of this mammary-associated T-bet +population throughout pregnancy and lactation. Understanding the dynamics of T-bet +cells and their anatomical localization within the mammary gland will help us decode how these cells impact the remodeling of the mammary epithelium during pregnancy and lactation. We propose that the remodeling of the mammary gland imparted by the immune system can also influence the transfer of immunity from mother to offspring, thereby affecting the development of offspring immunity.\u0000 This work was supported in part by intramural funds of NIAID, NIH.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85818527","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}

{"title":"Epigenetic mechanisms of epithelial – immune interactions that shape immune surveillance in the intestinal epithelium","authors":"Aybuke Garipcan, Onur Eskiocak, Santhilal Subhash, Kadir Ozler, Brian Yueh, C. Chung, Ilgin Ergin, Nelson Gautier, Jill Habel, Rachel Rubino, A. V. D. van der Velden, Semir Beyaz","doi":"10.4049/jimmunol.210.supp.150.04","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.150.04","url":null,"abstract":"\u0000 Immune surveillance of the intestinal epithelium is regulated by the reciprocal interactions between intestinal epithelial cells, immune system and microbiome. This highly specialized compartment maintains the tolerance against dietary products and commensal bacteria while protecting the epithelium against pathogens, cancer risk and tissue damage. While recent studies identified epigenetic mechanisms that orchestrate the self-renewal and differentiation of intestinal epithelial cells (IECs), little is known about the mechanisms that govern epithelial – immune interactions and how they influence immune surveillance and tissue regeneration. Here we dissect epithelial-intrinsic epigenetic features including transcription factors and co-activators that govern immune surveillance of intestinal epithelium using genetically engineered mouse models and autologous human patient-derived organoid – immune co-cultures. Ablation of epigenetic regulators that associate with immune interaction gene modules specifically in IECs dampens intraepithelial lymphocyte-mediated immune surveillance. We identified precise epigenetic mechanisms of epithelial – immune interactions including promoter and enhancer regulation by transcription factors and co-activators both in mice and humans. Finally, disruption of the epigenetic regulators that maintain epithelial – immune interactions lead to impaired responses in clinically-relevant mouse models of infection, tissue regeneration and cancer. These results establish a strong foundation towards understanding the epigenetic mechanisms that govern multi-cellular interactions within the barrier tissues in physiology or disease states.\u0000 Supported by grants from Mathers Foundation, STARR Cancer Consortium (I13-0052), The Mark Foundation for Cancer Research (20-028-EDV), NIH (P30CA045508-33), CZI Ancestry Network for the Human Cell Atlas","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86043050","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}