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1,549 results on '"Kuchroo, Vijay K"'

1. Neuropeptide signalling orchestrates T cell differentiation

Author

Hou, Yu, Sun, Linyu, LaFleur, Martin W., Huang, Linglin, Lambden, Conner, Thakore, Pratiksha I., Geiger-Schuller, Kathryn, Kimura, Kimitoshi, Yan, Longjun, Zang, Yue, Tang, Ruihan, Shi, Jingwen, Barilla, Rocky, Deng, Liwen, Subramanian, Ayshwarya, Wallrapp, Antonia, Choi, Hee Sun, Kye, Yoon-Chul, Ashenberg, Orr, Schiebinger, Geoffrey, Doench, John G., Chiu, Isaac M., Regev, Aviv, Sharpe, Arlene H., and Kuchroo, Vijay K.

Published
2024
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2. BACH2 regulates diversification of regulatory and proinflammatory chromatin states in TH17 cells

Author

Thakore, Pratiksha I., Schnell, Alexandra, Huang, Linglin, Zhao, Maryann, Hou, Yu, Christian, Elena, Zaghouani, Sarah, Wang, Chao, Singh, Vasundhara, Singaraju, Anvita, Krishnan, Rajesh Kumar, Kozoriz, Deneen, Ma, Sai, Sankar, Venkat, Notarbartolo, Samuele, Buenrostro, Jason D., Sallusto, Federica, Patsopoulos, Nikolaos A., Rozenblatt-Rosen, Orit, Kuchroo, Vijay K., and Regev, Aviv

Published
2024
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3. Droplet-based forward genetic screening of astrocyte–microglia cross-talk

Author

Wheeler, Michael A, Clark, Iain C, Lee, Hong-Gyun, Li, Zhaorong, Linnerbauer, Mathias, Rone, Joseph M, Blain, Manon, Akl, Camilo Faust, Piester, Gavin, Giovannoni, Federico, Charabati, Marc, Lee, Joon-Hyuk, Kye, Yoon-Chul, Choi, Joshua, Sanmarco, Liliana M, Srun, Lena, Chung, Elizabeth N, Flausino, Lucas E, Andersen, Brian M, Rothhammer, Veit, Yano, Hiroshi, Illouz, Tomer, Zandee, Stephanie EJ, Daniel, Carolin, Artis, David, Prinz, Marco, Abate, Adam R, Kuchroo, Vijay K, Antel, Jack P, Prat, Alexandre, and Quintana, Francisco J

Subjects
Neurosciences, Human Genome, Biotechnology, Genetics, 2.1 Biological and endogenous factors, Aetiology, Astrocytes, Genetic Testing, High-Throughput Screening Assays, Microfluidic Analytical Techniques, Microglia, Amphiregulin, Autocrine Communication, Gene Expression, Humans, General Science & Technology
Abstract

Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms.

Published
2023

6. Retraction: TIGIT predominantly regulates the immune response via regulatory T cells

Author

Kurtulus, Sema, Sakuishi, Kaori, Ngiow, Shin-Foong, Joller, Nicole, Tan, Dewar J., Teng, Michele W.L., Smyth, Mark J., Kuchroo, Vijay K., and Anderson, Ana C.

Subjects
Health care industry
Abstract

Original citation: J Clin Invest. 2015;125(11):4053-4062. https://doi.org/10.1172/JCI81187. Citation for this retraction: J Clin Invest. 2024;134(13):e183278. https://doi.org/10.1172/JCI183278. QIMR Berghofer Medical Research Institute recently notified the JCI of concerns regarding Figure 4B [...]

Published
2024

7. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Author

Sanmarco, Liliana M., Rone, Joseph M., Polonio, Carolina M., Fernandez Lahore, Gonzalo, Giovannoni, Federico, Ferrara, Kylynne, Gutierrez-Vazquez, Cristina, Li, Ning, Sokolovska, Anna, Plasencia, Agustin, Faust Akl, Camilo, Nanda, Payal, Heck, Evelin S., Li, Zhaorong, Lee, Hong-Gyun, Chao, Chun-Cheih, Rejano-Gordillo, Claudia M., Fonseca-Castro, Pedro H., Illouz, Tomer, Linnerbauer, Mathias, Kenison, Jessica E., Barilla, Rocky M., Farrenkopf, Daniel, Stevens, Nikolas A., Piester, Gavin, Chung, Elizabeth N., Dailey, Lucas, Kuchroo, Vijay K., Hava, David, Wheeler, Michael A., Clish, Clary, Nowarski, Roni, Balsa, Eduardo, Lora, Jose M., and Quintana, Francisco J.

Published
2023
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8. Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis

Author

Ozmadenci, Duygu, Narayanan, Jayanth S Shankara, Andrew, Jacob, Ojalill, Marjaana, Barrie, Allison M, Jiang, Shulin, Iyer, Samhita, Chen, Xiao Lei, Rose, Michael, Estrada, Valeria, Molinolo, Alfredo, Bertotto, Thomas, Mikulski, Zbigniew, McHale, Michael C, White, Rebekah R, Connolly, Denise C, Pachter, Jonathan A, Kuchroo, Vijay K, Stupack, Dwayne G, and Schlaepfer, David D

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Biotechnology, Immunotherapy, Rare Diseases, Cancer Genomics, Cancer, Genetics, Orphan Drug, Women's Health, Ovarian Cancer, Human Genome, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Carcinoma, Ovarian Epithelial, Female, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, Immunosuppression Therapy, Ligands, Mice, Ovarian Neoplasms, Receptors, Immunologic, high-grade serous ovarian cancer, immunotherapy, FAK, CD155, tertiary lymphoid structures
Abstract

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in ∼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC.

Published
2022

9. Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling

Author

Cadinu, Paolo, Sivanathan, Kisha N., Misra, Aditya, Xu, Rosalind J., Mangani, Davide, Yang, Evan, Rone, Joseph M., Tooley, Katherine, Kye, Yoon-Chul, Bod, Lloyd, Geistlinger, Ludwig, Lee, Tyrone, Mertens, Randall T., Ono, Noriaki, Wang, Gang, Sanmarco, Liliana, Quintana, Francisco J., Anderson, Ana C., Kuchroo, Vijay K., Moffitt, Jeffrey R., and Nowarski, Roni

Published
2024
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11. B-cell-specific checkpoint molecules that regulate anti-tumour immunity

Author

Bod, Lloyd, Kye, Yoon-Chul, Shi, Jingwen, Torlai Triglia, Elena, Schnell, Alexandra, Fessler, Johannes, Ostrowski, Stephen M., Von-Franque, Max Y., Kuchroo, Juhi R., Barilla, Rocky M., Zaghouani, Sarah, Christian, Elena, Delorey, Toni Marie, Mohib, Kanishka, Xiao, Sheng, Slingerland, Nadine, Giuliano, Christopher J., Ashenberg, Orr, Li, Zhaorong, Rothstein, David M., Fisher, David E., Rozenblatt-Rosen, Orit, Sharpe, Arlene H., Quintana, Francisco J., Apetoh, Lionel, Regev, Aviv, and Kuchroo, Vijay K.

Published
2023
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12. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity

Author

Wagner, Allon, Wang, Chao, Fessler, Johannes, DeTomaso, David, Avila-Pacheco, Julian, Kaminski, James, Zaghouani, Sarah, Christian, Elena, Thakore, Pratiksha, Schellhaass, Brandon, Akama-Garren, Elliot, Pierce, Kerry, Singh, Vasundhara, Ron-Harel, Noga, Douglas, Vivian Paraskevi, Bod, Lloyd, Schnell, Alexandra, Puleston, Daniel, Sobel, Raymond A, Haigis, Marcia, Pearce, Erika L, Soleimani, Manoocher, Clish, Clary, Regev, Aviv, Kuchroo, Vijay K, and Yosef, Nir

Subjects
Brain Disorders, Autoimmune Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Acetyltransferases, Adenosine Triphosphate, Aerobiosis, Algorithms, Animals, Autoimmunity, Chromatin, Citric Acid Cycle, Cytokines, Eflornithine, Encephalomyelitis, Autoimmune, Experimental, Epigenome, Fatty Acids, Glycolysis, Jumonji Domain-Containing Histone Demethylases, Mice, Inbred C57BL, Mitochondrial Membrane Transport Proteins, Models, Biological, Oxidation-Reduction, Putrescine, Single-Cell Analysis, T-Lymphocytes, Regulatory, Th17 Cells, Transcriptome, DFMO, T helper 17 cell, experimental autoimmune encephalomyelitis, immunometabolism, in silico metabolic modeling, multiple sclerosis, polyamines, putrescine, single cell transcriptomics, spermidine, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.

Published
2021

13. Author Correction: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

Author

Huang, Yu-Hwa, Zhu, Chen, Kondo, Yasuyuki, Anderson, Ana C., Gandhi, Amit, Russell, Andrew, Dougan, Stephanie K., Petersen, Britt-Sabina, Melum, Espen, Pertel, Thomas, Clayton, Kiera L., Raab, Monika, Chen, Qiang, Beauchemin, Nicole, Yazaki, Paul J., Pyzik, Michal, Ostrowski, Mario A., Glickman, Jonathan N., Rudd, Christopher E., Ploegh, Hidde L., Franke, Andre, Petsko, Gregory A., Kuchroo, Vijay K., and Blumberg, Richard S.

Published
2024
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15. Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS)

Author

Bewersdorf, Jan Philipp, Xie, Zhuoer, Bejar, Rafael, Borate, Uma, Boultwood, Jacqueline, Brunner, Andrew M., Buckstein, Rena, Carraway, Hetty E., Churpek, Jane E., Daver, Naval G., Porta, Matteo Giovanni Della, DeZern, Amy E., Fenaux, Pierre, Figueroa, Maria E., Gore, Steven D., Griffiths, Elizabeth A., Halene, Stephanie, Hasserjian, Robert P., Hourigan, Christopher S., Kim, Tae Kon, Komrokji, Rami, Kuchroo, Vijay K., List, Alan F., Loghavi, Sanam, Majeti, Ravindra, Odenike, Olatoyosi, Patnaik, Mrinal M., Platzbecker, Uwe, Roboz, Gail J., Sallman, David A., Santini, Valeria, Sanz, Guillermo, Sekeres, Mikkael A., Stahl, Maximilian, Starczynowski, Daniel T., Steensma, David P., Taylor, Justin, Abdel-Wahab, Omar, Xu, Mina L., Savona, Michael R., Wei, Andrew H., and Zeidan, Amer M.

Published
2023
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16. Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut

Author

Duan, Jinzhi, Matute, Juan D., Unger, Lukas W., Hanley, Thomas, Schnell, Alexandra, Lin, Xi, Krupka, Niklas, Griebel, Paul, Lambden, Conner, Sit, Brandon, Grootjans, Joep, Pyzik, Michal, Sommer, Felix, Kaiser, Sina, Falk-Paulsen, Maren, Grasberger, Helmut, Kao, John Y., Fuhrer, Tobias, Li, Hai, Paik, Donggi, Lee, Yunjin, Refetoff, Samuel, Glickman, Jonathan N., Paton, Adrienne W., Bry, Lynn, Paton, James C., Sauer, Uwe, Macpherson, Andrew J., Rosenstiel, Philip, Kuchroo, Vijay K., Waldor, Matthew K., Huh, Jun R., Kaser, Arthur, and Blumberg, Richard S.

Published
2023
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18. Induction of a colitogenic phenotype in Th1-like cells depends on interleukin-23 receptor signaling

Author

Pawlak, Mathias, DeTomaso, David, Schnell, Alexandra, Meyer zu Horste, Gerd, Lee, Youjin, Nyman, Jackson, Dionne, Danielle, Regan, Brianna M.L., Singh, Vasundhara, Delorey, Toni, Schramm, Markus A., Wang, Chao, Wallrapp, Antonia, Burkett, Patrick R., Riesenfeld, Samantha J., Anderson, Ana C., Regev, Aviv, Xavier, Ramnik J., Yosef, Nir, and Kuchroo, Vijay K.

Published
2022
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20. Antigen presentation safeguards the integrity of the hematopoietic stem cell pool

Author

Hernández-Malmierca, Pablo, Vonficht, Dominik, Schnell, Alexandra, Uckelmann, Hannah J., Bollhagen, Alina, Mahmoud, Mohamed A.A., Landua, Sophie-Luise, van der Salm, Elise, Trautmann, Christine L., Raffel, Simon, Grünschläger, Florian, Lutz, Raphael, Ghosh, Michael, Renders, Simon, Correia, Nádia, Donato, Elisa, Dixon, Karin O., Hirche, Christoph, Andresen, Carolin, Robens, Claudia, Werner, Paula S., Boch, Tobias, Eisel, David, Osen, Wolfram, Pilz, Franziska, Przybylla, Adriana, Klein, Corinna, Buchholz, Frank, Milsom, Michael D., Essers, Marieke A.G., Eichmüller, Stefan B., Hofmann, Wolf-Karsten, Nowak, Daniel, Hübschmann, Daniel, Hundemer, Michael, Thiede, Christian, Bullinger, Lars, Müller-Tidow, Carsten, Armstrong, Scott A., Trumpp, Andreas, Kuchroo, Vijay K., and Haas, Simon

Published
2022
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24. Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function

Author

He, Danyang, Xu, Heping, Zhang, Huiyuan, Tang, Ruihan, Lan, Yangning, Xing, Ruxiao, Li, Shaomin, Christian, Elena, Hou, Yu, Lorello, Paul, Caldarone, Barbara, Ding, Jiarui, Nguyen, Lan, Dionne, Danielle, Thakore, Pratiksha, Schnell, Alexandra, Huh, Jun R., Rozenblatt-Rosen, Orit, Regev, Aviv, and Kuchroo, Vijay K.

Published
2022
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28. Spatially organized multicellular immune hubs in human colorectal cancer

Author

Pelka, Karin, Hofree, Matan, Chen, Jonathan H., Sarkizova, Siranush, Pirl, Joshua D., Jorgji, Vjola, Bejnood, Alborz, Dionne, Danielle, Ge, William H., Xu, Katherine H., Chao, Sherry X., Zollinger, Daniel R., Lieb, David J., Reeves, Jason W., Fuhrman, Christopher A., Hoang, Margaret L., Delorey, Toni, Nguyen, Lan T., Waldman, Julia, Klapholz, Max, Wakiro, Isaac, Cohen, Ofir, Albers, Julian, Smillie, Christopher S., Cuoco, Michael S., Wu, Jingyi, Su, Mei-ju, Yeung, Jason, Vijaykumar, Brinda, Magnuson, Angela M., Asinovski, Natasha, Moll, Tabea, Goder-Reiser, Max N., Applebaum, Anise S., Brais, Lauren K., DelloStritto, Laura K., Denning, Sarah L., Phillips, Susannah T., Hill, Emma K., Meehan, Julia K., Frederick, Dennie T., Sharova, Tatyana, Kanodia, Abhay, Todres, Ellen Z., Jané-Valbuena, Judit, Biton, Moshe, Izar, Benjamin, Lambden, Conner D., Clancy, Thomas E., Bleday, Ronald, Melnitchouk, Nelya, Irani, Jennifer, Kunitake, Hiroko, Berger, David L., Srivastava, Amitabh, Hornick, Jason L., Ogino, Shuji, Rotem, Asaf, Vigneau, Sébastien, Johnson, Bruce E., Corcoran, Ryan B., Sharpe, Arlene H., Kuchroo, Vijay K., Ng, Kimmie, Giannakis, Marios, Nieman, Linda T., Boland, Genevieve M., Aguirre, Andrew J., Anderson, Ana C., Rozenblatt-Rosen, Orit, Regev, Aviv, and Hacohen, Nir

Published
2021
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29. Polyamine metabolism is a central determinant of helper T cell lineage fidelity

Author

Puleston, Daniel J., Baixauli, Francesc, Sanin, David E., Edwards-Hicks, Joy, Villa, Matteo, Kabat, Agnieszka M., Kamiński, Marcin M., Stanckzak, Michal, Weiss, Hauke J., Grzes, Katarzyna M., Piletic, Klara, Field, Cameron S., Corrado, Mauro, Haessler, Fabian, Wang, Chao, Musa, Yaarub, Schimmelpfennig, Lena, Flachsmann, Lea, Mittler, Gerhard, Yosef, Nir, Kuchroo, Vijay K., Buescher, Joerg M., Balabanov, Stefan, Pearce, Edward J., Green, Douglas R., and Pearce, Erika L.

Published
2021
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33. Autoimmunity and the microbiome.

Author

Cox, Laura M. and Kuchroo, Vijay K.

Subjects
*FECAL microbiota transplantation, *GUT microbiome, *TRANSCRIPTION factors, *AMINO acid derivatives, *THERAPEUTICS, *AUTOIMMUNE diseases
Abstract

This article examines the connection between the gut microbiome and autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The gut microbiome plays a significant role in shaping the immune system and regulating bodily functions. Various factors, such as genetics, age, diet, and geographical location, can impact the risk of developing autoimmune diseases and influence the composition of the gut microbiota. The article also explores the potential of fecal microbiota transplants as a therapeutic option for treating autoimmune diseases. Further research is needed to fully understand these interactions and develop effective treatments. [Extracted from the article]

Published
2024
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35. An IL-27-Driven Transcriptional Network Identifies Regulators of IL-10 Expression across T Helper Cell Subsets

Author

Zhang, Huiyuan, Madi, Asaf, Yosef, Nir, Chihara, Norio, Awasthi, Amit, Pot, Caroline, Lambden, Conner, Srivastava, Amitabh, Burkett, Patrick R., Nyman, Jackson, Christian, Elena, Etminan, Yasaman, Lee, Annika, Stroh, Helene, Xia, Junrong, Karwacz, Katarzyna, Thakore, Pratiksha I., Acharya, Nandini, Schnell, Alexandra, Wang, Chao, Apetoh, Lionel, Rozenblatt-Rosen, Orit, Anderson, Ana C., Regev, Aviv, and Kuchroo, Vijay K.

Published
2020
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36. Endogenous Glucocorticoid Signaling Regulates CD8+ T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment

Author

Acharya, Nandini, Madi, Asaf, Zhang, Huiyuan, Klapholz, Max, Escobar, Giulia, Dulberg, Shai, Christian, Elena, Ferreira, Michelle, Dixon, Karen O., Fell, Geoffrey, Tooley, Katherine, Mangani, Davide, Xia, Junrong, Singer, Meromit, Bosenberg, Marcus, Neuberg, Donna, Rozenblatt-Rosen, Orit, Regev, Aviv, Kuchroo, Vijay K., and Anderson, Ana C.

Published
2020
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37. Human regulatory memory B cells defined by expression of TIM-1 and TIGIT are dysfunctional in multiple sclerosis

Author

Varghese, Johnna F., primary, Kaskow, Belinda J., additional, von Glehn, Felipe, additional, Case, Junning, additional, Li, Zhenhua, additional, Julé, Amélie M., additional, Berdan, Emma, additional, Ho Sui, Shannan Janelle, additional, Hu, Yong, additional, Krishnan, Rajesh, additional, Chitnis, Tanuja, additional, Kuchroo, Vijay K., additional, Weiner, Howard L., additional, and Baecher-Allan, Clare Mary, additional

Published
2024
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38. IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy

Author

Krueger, James G., primary, Eyerich, Kilian, additional, Kuchroo, Vijay K., additional, Ritchlin, Christopher T., additional, Abreu, Maria T., additional, Elloso, M. Merle, additional, Fourie, Anne, additional, Fakharzadeh, Steven, additional, Sherlock, Jonathan P., additional, Yang, Ya-Wen, additional, Cua, Daniel J., additional, and McInnes, Iain B., additional

Published
2024
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40. T Cell–Independent Mechanisms Associated with Neutrophil Extracellular Trap Formation and Selective Autophagy in IL-17A–Mediated Epidermal Hyperplasia

Author

Suzuki, Erika, Maverakis, Emanual, Sarin, Ritu, Bouchareychas, Laura, Kuchroo, Vijay K, Nestle, Frank O, and Adamopoulos, Iannis E

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, 2.1 Biological and endogenous factors, Animals, Autophagy, Epithelium, Extracellular Traps, Homeodomain Proteins, Hyperplasia, Interleukin-17, Mice, Mice, Knockout, Receptors, Antigen, T-Cell, gamma-delta, Receptors, Interleukin, T-Lymphocytes, Immunology, Biochemistry and cell biology
Abstract

IL-17A has been strongly associated with epidermal hyperplasia in many cutaneous disorders. However, because IL-17A is mainly produced by αβ and γδT cells in response to IL-23, the role of T cells and IL-23 has overshadowed any IL-17A-independent actions. In this article, we report that IL-17A gene transfer induces epidermal hyperplasia in Il23r-/-Rag1-/-- and Tcrδ-deficient mice, which can be prevented by neutrophil depletion. Moreover, adoptive transfer of CD11b+Gr-1hi cells, after IL-17A gene transfer, was sufficient to phenocopy the disease. We further show that the IL-17A-induced pathology was prevented in transgenic mice with impaired neutrophil extracellular trap formation and/or neutrophils with conditional deletion of the master regulator of selective autophagy, Wdfy3. Our data demonstrate a novel T cell-independent mechanism that is associated with neutrophil extracellular trap formation and selective autophagy in IL-17A-mediated epidermal hyperplasia.

Published
2016

41. Gut-Innervating Nociceptor Neurons Regulate Peyer’s Patch Microfold Cells and SFB Levels to Mediate Salmonella Host Defense

Author

Lai, Nicole Y., Musser, Melissa A., Pinho-Ribeiro, Felipe A., Baral, Pankaj, Jacobson, Amanda, Ma, Pingchuan, Potts, David E., Chen, Zuojia, Paik, Donggi, Soualhi, Salima, Yan, Yiqing, Misra, Aditya, Goldstein, Kaitlin, Lagomarsino, Valentina N., Nordstrom, Anja, Sivanathan, Kisha N., Wallrapp, Antonia, Kuchroo, Vijay K., Nowarski, Roni, Starnbach, Michael N., Shi, Hailian, Surana, Neeraj K., An, Dingding, Wu, Chuan, Huh, Jun R., Rao, Meenakshi, and Chiu, Isaac M.

Published
2020
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45. Oct1 and OCA-B are selectively required for CD4 memory T cell function

Author

Shakya, Arvind, Goren, Alon, Shalek, Alex, German, Cody N, Snook, Jeremy, Kuchroo, Vijay K, Yosef, Nir, Chan, Raymond C, Regev, Aviv, Williams, Matthew A, and Tantin, Dean

Subjects
Genetics, Biotechnology, HIV/AIDS, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, Animals, Blotting, Western, CD4-Positive T-Lymphocytes, Cells, Cultured, Gene Expression, Host-Pathogen Interactions, Immunologic Memory, Interferon-gamma, Interleukin-2, Jumonji Domain-Containing Histone Demethylases, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Mice, Knockout, Octamer Transcription Factor-1, Protein Binding, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Trans-Activators, Medical and Health Sciences, Immunology
Abstract

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory.

Published
2015

46. Recipient T cell TIM-3 and hepatocyte galectin-9 signalling protects mouse liver transplants against ischemia-reperfusion injury.

Author

Liu, Yuanxing, Ji, Haofeng, Zhang, Yu, Shen, Xiuda, Gao, Feng, He, Xiangyi, Li, Gabriella A, Busuttil, Ronald W, Kuchroo, Vijay K, and Kupiec-Weglinski, Jerzy W

Subjects
Neutrophils, T-Lymphocytes, Macrophages, Hepatocytes, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Mice, Reperfusion Injury, Disease Models, Animal, Allopurinol, Insulin, Raffinose, Glutathione, Galectins, Receptors, Virus, Adenosine, Organ Preservation Solutions, Organ Preservation, Liver Transplantation, Lymphocyte Activation, Signal Transduction, Apoptosis, Cell Differentiation, Male, Immunity, Innate, Mice, 129 Strain, In Vitro Techniques, Hepatitis A Virus Cellular Receptor 2, Galectin-9, Innate immunity, Ischemia-reperfusion injury, Liver, Orthotopic liver transplantation, TIM-3, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Organ Transplantation, Transplantation, Liver Disease, Good Health and Well Being, Clinical Sciences, Public Health and Health Services, Gastroenterology & Hepatology
Abstract

Background & aimsBy binding to T cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation.MethodsWe used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20 h at 4°C in UW solution) and syngeneic orthotopic liver transplantation (OLT).ResultsOrthotopic liver transplants in WT or TIM-3Tg→TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg→WT groups were susceptible to IRI. TIM-3 induction in circulating CD4+ T cells of the recipient: (1) depressed T-bet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD-1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we documented for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in vivo and in vitro. Moreover, exogenous recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells.ConclusionsHarnessing TIM-3/Gal-9 signalling at the T cell-hepatocyte interface facilitates homeostasis in IR-stressed orthotopic liver transplants. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR-resistance. Negative regulation by recipient TIM-3+CD4+ cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients.

Published
2015

47. Genetic and epigenetic fine mapping of causal autoimmune disease variants

Author

Farh, Kyle Kai-How, Marson, Alexander, Zhu, Jiang, Kleinewietfeld, Markus, Housley, William J, Beik, Samantha, Shoresh, Noam, Whitton, Holly, Ryan, Russell JH, Shishkin, Alexander A, Hatan, Meital, Carrasco-Alfonso, Marlene J, Mayer, Dita, Luckey, C John, Patsopoulos, Nikolaos A, De Jager, Philip L, Kuchroo, Vijay K, Epstein, Charles B, Daly, Mark J, Hafler, David A, and Bernstein, Bradley E

Subjects
Immunization, Human Genome, Vaccine Related, Autoimmune Disease, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, Inflammatory and immune system, Autoimmune Diseases, Base Sequence, Chromatin, Consensus Sequence, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Genome-Wide Association Study, Humans, Nucleotide Motifs, Organ Specificity, Polymorphism, Single Nucleotide, T-Lymphocytes, Transcription Factors, General Science & Technology
Abstract

Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

Published
2015

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