Leonie Brockmann, Alexander Tran, Yiming Huang, Madeline Edwards, Carlotta Ronda, Harris H Wang, Ivaylo I Ivanov
Commensal microbes induce cytokine-producing effector tissue-resident CD4+ T cells, but the function of these T cells in mucosal homeostasis is not well understood. Here, we report that commensal-specific intestinal Th17 cells possess an anti-inflammatory phenotype marked by expression of interleukin (IL)-10 and co-inhibitory receptors. The anti-inflammatory phenotype of gut-resident commensal-specific Th17 cells was driven by the transcription factor c-MAF. IL-10-producing commensal-specific Th17 cells were heterogeneous and derived from a TCF1+ gut-resident progenitor Th17 cell population...
November 29, 2023: Immunity
Michael Korenkov, Matthias Zehner, Hadas Cohen-Dvashi, Aliza Borenstein-Katz, Lisa Kottege, Hanna Janicki, Kanika Vanshylla, Timm Weber, Henning Gruell, Manuel Koch, Ron Diskin, Christoph Kreer, Florian Klein
Somatic hypermutation (SHM) drives affinity maturation and continues over months in SARS-CoV-2-neutralizing antibodies (nAbs). However, several potent SARS-CoV-2 antibodies carry no or only a few mutations, leaving the question of how ongoing SHM affects neutralization unclear. Here, we reverted variable region mutations of 92 antibodies and tested their impact on SARS-CoV-2 binding and neutralization. Reverting higher numbers of mutations correlated with decreasing antibody functionality. However, for some antibodies, including antibodies of the public clonotype VH1-58, neutralization of Wu01 remained unaffected...
November 22, 2023: Immunity
Tarek Taifour, Sherif Samer Attalla, Dongmei Zuo, Yu Gu, Virginie Sanguin-Gendreau, Hailey Proud, Emilie Solymoss, Tung Bui, Hellen Kuasne, Vasilios Papavasiliou, Chun Geun Lee, Suchitra Kamle, Peter M Siegel, Jack A Elias, Morag Park, William J Muller
In triple-negative breast cancer (TNBC), stromal restriction of CD8+ T cells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint blockade (ICB). To identify mediators of T cell stromal restriction, we profiled murine breast tumors lacking the transcription factor Stat3, which is commonly hyperactive in breast cancers and promotes an immunosuppressive tumor microenvironment. Expression of the cytokine Chi3l1 was decreased in Stat3-/- tumors. CHI3L1 expression was elevated in human TNBCs and other solid tumors exhibiting T cell stromal restriction...
November 18, 2023: Immunity
Ruoxi Zhang, Chunhua Yu, Herbert J Zeh, Haichao Wang, Guido Kroemer, Daniel J Klionsky, Timothy R Billiar, Rui Kang, Daolin Tang
Extensive studies demonstrate the importance of the STING1 (also known as STING) protein as a signaling hub that coordinates immune and autophagic responses to ectopic DNA in the cytoplasm. Here, we report a nuclear function of STING1 in driving the activation of the transcription factor aryl hydrocarbon receptor (AHR) to control gut microbiota composition and homeostasis. This function was independent of DNA sensing and autophagy and showed competitive inhibition with cytoplasmic cyclic guanosine monophosphate (GMP)-AMP synthase (CGAS)-STING1 signaling...
November 15, 2023: Immunity
Hai-Rong Peng, Jia-Qian Qiu, Qin-Ming Zhou, Yu-Kai Zhang, Qiao-Yu Chen, Yan-Qing Yin, Wen Su, Shui Yu, Ya-Ting Wang, Yuping Cai, Ming-Na Gu, Hao-Hao Zhang, Qing-Qing Sun, Gang Hu, Yi-Wen Wu, Jun Liu, Sheng Chen, Zheng-Jiang Zhu, Xin-Yang Song, Jia-Wei Zhou
Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity...
November 15, 2023: Immunity
Marina Terekhova, Amanda Swain, Pavla Bohacova, Ekaterina Aladyeva, Laura Arthur, Anwesha Laha, Denis A Mogilenko, Samantha Burdess, Vladimir Sukhov, Denis Kleverov, Barbora Echalar, Petr Tsurinov, Roman Chernyatchik, Kamila Husarcikova, Maxim N Artyomov
Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the systematic understanding of human aging. Here, using single-cell RNA/T cell receptor (TCR)/BCR-seq with protein feature barcoding, we profiled 317 samples from 166 healthy individuals aged 25-85 years old. From this, we generated a dataset from ∼2 million cells that described 55 subpopulations of blood immune cells. Twelve subpopulations changed with age, including the accumulation of GZMK+ CD8+ T cells and HLA-DR+ CD4+ T cells...
November 5, 2023: Immunity
Ruoke Wang, Yang Han, Rui Zhang, Jiayi Zhu, Xuanyu Nan, Yaping Liu, Ziqing Yang, Bini Zhou, Jinfang Yu, Zichun Lin, Jinqian Li, Peng Chen, Yangjunqi Wang, Yujie Li, Dongsheng Liu, Xuanling Shi, Xinquan Wang, Qi Zhang, Yuhe R Yang, Taisheng Li, Linqi Zhang
The 2003 severe acute respiratory syndrome coronavirus (SARS-CoV-1) causes more severe disease than SARS-CoV-2, which is responsible for COVID-19. However, our understanding of antibody response to SARS-CoV-1 infection remains incomplete. Herein, we studied the antibody responses in 25 SARS-CoV-1 convalescent patients. Plasma neutralization was higher and lasted longer in SARS-CoV-1 patients than in severe SARS-CoV-2 patients. Among 77 monoclonal antibodies (mAbs) isolated, 60 targeted the receptor-binding domain (RBD) and formed 7 groups (RBD-1 to RBD-7) based on their distinct binding and structural profiles...
October 27, 2023: Immunity
Yulong Wei, Timothy C Davenport, Jack A Collora, Haocong Katherine Ma, Delia Pinto-Santini, Javier Lama, Ricardo Alfaro, Ann Duerr, Ya-Chi Ho
Understanding how HIV-1-infected cells proliferate and persist is key to HIV-1 eradication, but the heterogeneity and rarity of HIV-1-infected cells hamper mechanistic interrogations. Here, we used single-cell DOGMA-seq to simultaneously capture transcription factor accessibility, transcriptome, surface proteins, HIV-1 DNA, and HIV-1 RNA in memory CD4+ T cells from six people living with HIV-1 during viremia and after suppressive antiretroviral therapy. We identified increased transcription factor accessibility in latent HIV-1-infected cells (RORC) and transcriptionally active HIV-1-infected cells (interferon regulatory transcription factor [IRF] and activator protein 1 [AP-1])...
October 26, 2023: Immunity
Subir Biswas, Gunjan Mandal, Carmen M Anadon, Ricardo A Chaurio, Luis U Lopez-Bailon, Mate Z Nagy, Jessica A Mine, Kay Hänggi, Kimberly B Sprenger, Patrick Innamarato, Carly M Harro, John J Powers, Joseph Johnson, Bin Fang, Mostafa Eysha, Xiaolin Nan, Roger Li, Bradford A Perez, Tyler J Curiel, Xiaoqing Yu, Paulo C Rodriguez, Jose R Conejo-Garcia
Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses...
October 26, 2023: Immunity
Yanfei Hou, Zhimeng Wang, Peiyuan Liu, Xubiao Wei, Zhengyin Zhang, Shilong Fan, Lulu Zhang, Fangping Han, Yikang Song, Ling Chu, Conggang Zhang
Lipid metabolism has been associated with the cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) stimulator of interferon genes (STING) DNA-sensing pathway, but our understanding of how these signals are integrated into a cohesive immunometabolic program is lacking. Here, we have identified liver X receptor (LXR) agonists as potent inhibitors of STING signaling. We show that stimulation of lipid metabolism by LXR agonists specifically suppressed cyclic GMP-AMP (cGAMP)-STING signaling. Moreover, we developed cyclic dinucleotide-conjugated beads to biochemically isolate host effectors for cGAMP inhibition, and we found that LXR ligands stimulated the expression of sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A), which is a 2'3'-cGAMP-degrading enzyme...
October 20, 2023: Immunity
Polly Matzinger, Olivier Lantz
No abstract text is available yet for this article.
October 14, 2023: Immunity
Chunyuan Zhao, Yunjin Ma, Minghui Zhang, Xiaoyan Gao, Wenbo Liang, Ying Qin, Yue Fu, Mutian Jia, Hui Song, Chengjiang Gao, Wei Zhao
Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses...
October 8, 2023: Immunity
Markus Müller, Florian Huber, Marion Arnaud, Anne I Kraemer, Emma Ricart Altimiras, Justine Michaux, Marie Taillandier-Coindard, Johanna Chiffelle, Baptiste Murgues, Talita Gehret, Aymeric Auger, Brian J Stevenson, George Coukos, Alexandre Harari, Michal Bassani-Sternberg
The accurate selection of neoantigens that bind to class I human leukocyte antigen (HLA) and are recognized by autologous T cells is a crucial step in many cancer immunotherapy pipelines. We reprocessed whole-exome sequencing and RNA sequencing (RNA-seq) data from 120 cancer patients from two external large-scale neoantigen immunogenicity screening assays combined with an in-house dataset of 11 patients and identified 46,017 somatic single-nucleotide variant mutations and 1,781,445 neo-peptides, of which 212 mutations and 178 neo-peptides were immunogenic...
October 4, 2023: Immunity
Lihong Liu, Ryan G Casner, Yicheng Guo, Qian Wang, Sho Iketani, Jasper Fuk-Woo Chan, Jian Yu, Bernadeta Dadonaite, Manoj S Nair, Hiroshi Mohri, Eswar R Reddem, Shuofeng Yuan, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Kwok-Yung Yuen, Zizhang Sheng, Yaoxing Huang, Jesse D Bloom, Lawrence Shapiro, David D Ho
SARS-CoV-2 continues to evolve, with many variants evading clinically authorized antibodies. To isolate monoclonal antibodies (mAbs) with broadly neutralizing capacities against the virus, we screened serum samples from convalescing COVID-19 patients. We isolated two mAbs, 12-16 and 12-19, which neutralized all SARS-CoV-2 variants tested, including the XBB subvariants, and prevented infection in hamsters challenged with Omicron BA.1 intranasally. Structurally, both antibodies targeted a conserved quaternary epitope located at the interface between the N-terminal domain and subdomain 1, uncovering a site of vulnerability on SARS-CoV-2 spike...
September 26, 2023: Immunity
Sangya Agarwal, M Angela Aznar, Andrew J Rech, Charly R Good, Shunichiro Kuramitsu, Tong Da, Mercy Gohil, Linhui Chen, Seok-Jae Albert Hong, Pranali Ravikumar, Austin K Rennels, January Salas-Mckee, Weimin Kong, Marco Ruella, Megan M Davis, Gabriela Plesa, Joseph A Fraietta, David L Porter, Regina M Young, Carl H June
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due to poor autologous T cell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR T cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR T cells...
September 21, 2023: Immunity
Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel
In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses...
September 8, 2023: Immunity
Yang Zang, Shaorui Liu, Zebing Rao, Yinsheng Wang, Boya Zhang, Hui Li, Yingjiao Cao, Jie Zhou, Zhuxia Shen, Shengzhong Duan, Danyang He, Heping Xu
Group 2 innate lymphoid cells (ILC2s) are crucial in promoting type 2 inflammation that contributes to both anti-parasite immunity and allergic diseases. However, the molecular checkpoints in ILC2s that determine whether to immediately launch a proinflammatory response are unknown. Here, we found that retinoid X receptor gamma (Rxrg) was highly expressed in small intestinal ILC2s and rapidly suppressed by alarmin cytokines. Genetic deletion of Rxrg did not impact ILC2 development but facilitated ILC2 responses and the tissue inflammation induced by alarmins...
September 6, 2023: Immunity
Ruipeng Lei, Wooseob Kim, Huibin Lv, Zongjun Mou, Michael J Scherm, Aaron J Schmitz, Jackson S Turner, Timothy J C Tan, Yiquan Wang, Wenhao O Ouyang, Weiwen Liang, Joel Rivera-Cardona, Chuyun Teo, Claire S Graham, Christopher B Brooke, Rachel M Presti, Chris K P Mok, Florian Krammer, Xinghong Dai, Ali H Ellebedy, Nicholas C Wu
There is growing appreciation for neuraminidase (NA) as an influenza vaccine target; however, its antigenicity remains poorly characterized. In this study, we isolated three broadly reactive N2 antibodies from the plasmablasts of a single vaccinee, including one that cross-reacts with NAs from seasonal H3N2 strains spanning five decades. Although these three antibodies have diverse germline usages, they recognize similar epitopes that are distant from the NA active site and instead involve the highly conserved underside of NA head domain...
November 14, 2023: Immunity
Matthias Zehner, Mira Alt, Artem Ashurov, Jory A Goldsmith, Rebecca Spies, Nina Weiler, Justin Lerma, Lutz Gieselmann, Dagmar Stöhr, Henning Gruell, Eric P Schultz, Christoph Kreer, Linda Schlachter, Hanna Janicki, Kerstin Laib Sampaio, Cora Stegmann, Michelle D Nemetchek, Sabrina Dähling, Leon Ullrich, Ulf Dittmer, Oliver Witzke, Manuel Koch, Brent J Ryckman, Ramin Lotfi, Jason S McLellan, Adalbert Krawczyk, Christian Sinzger, Florian Klein
Human cytomegalovirus (HCMV) can cause severe diseases in fetuses, newborns, and immunocompromised individuals. Currently, no vaccines are approved, and treatment options are limited. Here, we analyzed the human B cell response of four HCMV top neutralizers from a cohort of 9,000 individuals. By single-cell analyses of memory B cells targeting the pentameric and trimeric HCMV surface complexes, we identified vulnerable sites on the shared gH/gL subunits as well as complex-specific subunits UL128/130/131A and gO...
November 14, 2023: Immunity
Mytrang H Do, Wei Shi, Liangliang Ji, Erik Ladewig, Xian Zhang, Raghvendra M Srivastava, Kristelle J Capistrano, Chaucie Edwards, Isha Malik, Briana G Nixon, Efstathios G Stamatiades, Ming Liu, Shun Li, Peng Li, Chun Chou, Ke Xu, Ting-Wei Hsu, Xinxin Wang, Timothy A Chan, Christina S Leslie, Ming O Li
Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes...
November 14, 2023: Immunity
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