Thorsten Joeris, Cristina Gomez-Casado, Petra Holmkvist, Simon J Tavernier, Aaron Silva-Sanchez, Luisa Klotz, Troy D Randall, Allan M Mowat, Knut Kotarsky, Bernard Malissen, William W Agace
Although CD8+ T cell tolerance to tissue-specific antigen (TSA) is essential for host homeostasis, the mechanisms underlying peripheral cross-tolerance and whether they may differ between tissue sites remain to be fully elucidated. Here, we demonstrate that peripheral cross-tolerance to intestinal epithelial cell (IEC)-derived antigen involves the generation and suppressive function of FoxP3+ CD8+ T cells. FoxP3+ CD8+ Treg generation was dependent on intestinal cDC1, whose absence led to a break of tolerance and epithelial destruction...
June 4, 2021: Science Immunology
Byung-Seok Kim, Da-Sol Kuen, Choong-Hyun Koh, Hyung-Don Kim, Seon Hee Chang, Sehui Kim, Yoon Kyung Jeon, Young-Jun Park, Garam Choi, Jiyeon Kim, Keon Wook Kang, Hye Young Kim, Suk-Jo Kang, Shin Hwang, Eui-Cheol Shin, Chang-Yuil Kang, Chen Dong, Yeonseok Chung
BACKGROUND: Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) remain unclear. METHODS: To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8+ TILs in Il17a -/- mice, Il17a Cre R26 DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice...
June 2021: Journal for Immunotherapy of Cancer
Theresa Dornieden, Arne Sattler, Anna Pascual Reguant, Annkathrin Ruhm, Lion Thiel, Yasmin Bergmann, Linda Thole, Ralf Köhler, Anja Kühl, Anja Hauser, Senguel Boral, Frank Friedersdorff, Katja Kotsch
BACKGROUND: Tissue-resident memory (TRM ) T cells are known to be important for the first line of defense in mucosa-associated tissues. However, the composition, localization, effector function, and specificity of TRM T cells in the human kidney and their relevance for renal pathology have not been investigated. METHODS: Lymphocytes derived from blood, renal peri-tumor samples, and tumor samples were phenotypically and functionally assessed by applying flow cytometry and highly advanced histology (Multi-Epitope Ligand Cartography) methods...
June 1, 2021: Journal of the American Society of Nephrology: JASN
Karin Enderle, Martin Dinkel, Eva-Maria Spath, Benjamin Schmid, Sebastian Zundler, Philipp Tripal, Markus F Neurath, Kai Hildner, Clemens Neufert
Intraepithelial lymphocytes (IEL) are widely distributed within the small intestinal epithelial cell (IEC) layer and represent one of the largest T cell pools of the body. While implicated in the pathogenesis of intestinal inflammation, detailed insight especially into the cellular cross-talk between IELs and IECs is largely missing in part due to lacking methodologies to monitor this interaction. To overcome this shortcoming, we employed and validated a murine IEL-IEC (organoids) ex vivo co-culture model system...
May 13, 2021: International Journal of Molecular Sciences
Christina Hartl, Jürgen Finke, Peter Hasselblatt, Wolfgang Kreisel, Annette Schmitt-Graeff
OBJECTIVES: Chronic diarrhea, villous atrophy and/or increased intraepithelial T-lymphocytes (IEL) occur in many inflammatory disorders including celiac disease (CD). However, a definite diagnosis is difficult to make in some patients despite an extensive diagnostic work-up. Clinical outcomes and histological phenotypes of such patients we refer to as unclassifiable enteropathy (UEP) remain unclear. MATERIAL AND METHODS: We performed a retrospective single-center analysis of patients with chronic diarrhea, weight loss and increased IEL...
May 31, 2021: Scandinavian Journal of Gastroenterology
Alex KleinJan, Menno van Nimwegen, Karolina Leman, Ke-Xin Wen, Louis Boon, Rudi W Hendriks
Objective: To study airway pathophysiology and the role of dendritic cells (DCs) and IL-17 receptor (IL-17R) signals in a mouse model for CBD. Methods: Here, we present a CBD mouse model in which mice were exposed to beryllium during three weeks. We also exposed IL-17R-deficient mice and mice in which DCs were depleted. Results: Eight weeks after the initial beryllium exposure, an inflammatory response was detected in the lungs. Mice displayed inflammation of the lower airways that included focal dense infiltrates, granuloma-like foci, and tertiary lymphoid structure (TLS) containing T cells, B cells, and germinal centers...
2021: Mediators of Inflammation
Farah Hasan, Yulun Chiu, Rebecca M Shaw, Junmei Wang, Cassian Yee
Tissue-resident memory T cells (TRM) provide frontline defense against infectious diseases and contribute to antitumor immunity; however, aside from the necessity of TGF-β, knowledge regarding TRM-inductive cues remains incomplete, particularly for human cells. Oxygen tension is an environmental cue that distinguishes peripheral tissues from the circulation, and here, we demonstrate that differentiation of human CD8+ T cells in the presence of hypoxia and TGF-β1 led to the development of a TRM phenotype, characterized by a greater than 5-fold increase in CD69+CD103+ cells expressing human TRM hallmarks and enrichment for endogenous human TRM gene signatures, including increased adhesion molecule expression and decreased expression of genes involved in recirculation...
May 24, 2021: JCI Insight
Xavier Troussard, Elsa Maitre, Jérôme Paillassa
Hairy cell leukemia is a rare form of leukemia: three hundred new cases are diagnosed each year in France. The diagnosis is based on: (1) morphological examination of the blood and bone marrow smear, (2) analysis by flow cytometry of hairy cells, which express three or the four following markers: CD11c, CD25, CD103 and CD123, (3) identification of the BRAFV600E mutation, a true molecular marker of the disease. The management of treatment has evolved considerably in recent years. As of today, the purine analogues remain the standard treatment in the first line...
May 19, 2021: Bulletin du Cancer
Lei Bao, Changfu Hao, Juan Wang, Feifei Guo, Zihan Geng, Di Wang, Youliang Zhao, Yiping Li, Wu Yao
Exposure to sensitizer has been suggested to be hazardous to human health, evaluation the sensitization of sensitizer is particularly important and urgently needed. Dendritic cells (DCs) exert an irreplaceable function in immunity, and the T cell receptor (TCR) repertoire is key to ensuring immune response to foreign antigens. We hypothesized that a co-culture model of human monocyte-derived dendritic cells (Mo-DCs) and T cells could be employed to evaluate the sensitization of DNCB. An experimental model of DNCB-induced sensitization in rat was employed to examine alterations of cluster of differentiation CD103+ DCs and T cells...
May 18, 2021: Ecotoxicology and Environmental Safety
Hyeon-Jung Gu, Shinyoung Song, Joo Young Roh, YunJae Jung, Hee Joo Kim
BACKGROUND: Tissue resident memory T cells (TRMs) persist long-term in peripheral tissues without recirculation, triggering an immediate protective inflammatory state upon the re-recognition of the antigen. Despite evidence incriminating the dysregulation of TRMs in autoimmune diseases, few studies have examined their expression in cutaneous lupus erythematosus (CLE). OBJECTIVES: We aimed to examine whether there are differences among TRM populations in CLE depending on different clinical conditions, such as the CLE subtype or association with systemic lupus erythematosus, and to determine the effect of type I interferon (IFN) on the development of TRMs in CLE...
May 20, 2021: Lupus
Regina Aleksonienė, Justinas Besusparis, Vygantas Gruslys, Laimutė Jurgauskienė, Aida Laurinavičienė, Arvydas Laurinavičius, Radvilė Malickaitė, Jolita Norkūnienė, Rolandas Zablockis, Edvardas Žurauskas, Edvardas Danila
Background: The mechanisms driving the transition from inflammation to fibrosis in sarcoidosis patients are poorly understood; prognostic features are lacking. Immune cell profiling may provide insights into pathogenesis and prognostic factors of the disease. This study aimed to establish associations in simultaneous of lymphocyte subset profiles in the blood, bronchoalveolar lavage fluid (BALF), and lung biopsy tissue in the patients with newly diagnosed sarcoidosis. Methods: A total of 71 sarcoid patients (SPs) and 20 healthy controls (HCs) were enrolled into the study...
April 2021: Journal of Thoracic Disease
Luca Hensen, Patricia T Illing, E Bridie Clemens, Thi H O Nguyen, Marios Koutsakos, Carolien E van de Sandt, Nicole A Mifsud, Andrea T Nguyen, Christopher Szeto, Brendon Y Chua, Hanim Halim, Simone Rizzetto, Fabio Luciani, Liyen Loh, Emma J Grant, Phillipa M Saunders, Andrew G Brooks, Steve Rockman, Tom C Kotsimbos, Allen C Cheng, Michael Richards, Glen P Westall, Linda M Wakim, Thomas Loudovaris, Stuart I Mannering, Michael Elliott, Stuart G Tangye, David C Jackson, Katie L Flanagan, Jamie Rossjohn, Stephanie Gras, Jane Davies, Adrian Miller, Steven Y C Tong, Anthony W Purcell, Katherine Kedzierska
Indigenous people worldwide are at high risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. Here, we define CD8+ T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identify immunodominant protective CD8+ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2550-558 -specific CD8+ T cells being cross-reactive between IAV and IBV...
May 18, 2021: Nature Communications
Taiki Moriya, Kurumi Kitagawa, Yuuki Hayakawa, Hiroaki Hemmi, Tsuneyasu Kaisho, Satoshi Ueha, Ryoyo Ikebuchi, Ippei Yasuda, Yasutaka Nakanishi, Tetsuya Honda, Koji Matsushima, Kenji Kabashima, Mizuki Ueda, Yutaka Kusumoto, Tatyana Chtanova, Michio Tomura
Immunogenic tumor cell death enhances anti-tumor immunity. However, the mechanisms underlying this effect are incompletely understood. We established a system to induce tumor cell death in situ and investigated its effect on dendritic cell (DC) migration and T cell responses using intravital photolabeling in mice expressing KikGR photoconvertible protein. We demonstrate that tumor cell death induces phagocytosis of tumor cells by tumor-infiltrating (Ti)-DCs, and HMGB1-TLR4 and ATP-P2X7 receptor signaling-dependent Ti-DC emigration to draining lymph nodes (dLNs)...
May 21, 2021: IScience
Madeleine Pj White, Danielle J Smyth, Laura Cook, Steven F Ziegler, Megan K Levings, Rick M Maizels
Transforming growth factor-beta (TGF-β) family proteins mediate many vital biological functions in growth, development and regulation of the immune system. TGF-β itself controls immune homeostasis and inflammation, including conversion of naïve CD4+ T cells into Foxp3+ regulatory T cells (Tregs) in the presence of IL-2 and T cell receptor ligands. The helminth parasite Heligmosomoides polygyrus exploits this pathway through a structurally novel TGF-β mimic (Hp-TGM), which binds to mammalian TGF-β receptors and induces Tregs...
May 14, 2021: Immunology and Cell Biology
Álvaro de Mingo Pulido, Kay Hänggi, Daiana P Celias, Alycia Gardner, Jie Li, Bruna Batista-Bittencourt, Eslam Mohamed, Jimena Trillo-Tinoco, Olabisi Osunmakinde, Reymi Peña, Alexis Onimus, Tsuneyasu Kaisho, Johanna Kaufmann, Kristen McEachern, Hatem Soliman, Vincent C Luca, Paulo C Rodriguez, Xiaoqing Yu, Brian Ruffell
Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. TIM-3 inhibits production of the chemokine CXCL9 by XCR1+ classical dendritic cells (cDC1), thereby limiting antitumor immunity in mammary carcinomas. We found that increased CXCL9 expression by splenic cDC1s upon TIM-3 blockade required type I interferons and extracellular DNA. Chemokine expression as well as combinatorial efficacy of TIM-3 blockade and paclitaxel chemotherapy were impaired by deletion of Cgas and Sting...
May 5, 2021: Immunity
Sifei Yu, Suihua Lao, Binyan Yang, Changyou Wu
Tissue-resident memory T (TRM ) cells are well known to play critical roles in peripheral tissues during virus infection and tumor immunology. Our previous studies indicated that CD69+ CD4+ and CD69+ CD8+ T cells in tuberculous pleural effusion (TPE) were antigen-specific memory T cells. However, the phenotypical and functional characteristics of CD8+ TRM cells in tuberculosis remain unknown. We found that CD103+ CD8+ T cells were the predominant subset of CD103+ lymphocytes in TPE; both CD103 and CD69 expressed on memory CD8+ T cells from TPE were significantly increased compared with those from paired peripheral blood...
2021: Journal of Immunology Research
Mickey V Patel, Zheng Shen, Marta Rodriguez-Garcia, Edward J Usherwood, Laura J Tafe, Charles R Wira
Endometrial cancer is the most common gynecological cancer. To investigate how it suppresses host immune function, we isolated CD8+ T cells from endometrial endometroid carcinomas and adjacent non-cancerous endometrium and determined if the tumor environment regulates cytotoxic capacity. Endometrial carcinomas had increased numbers of CD8+ T cells compared to adjacent non-cancerous endometrium. Tumor CD8+ T cells expressed significantly less granzyme A (GZA), B (GZB), and PD-1 than those in adjacent non-cancerous tissues and also had significantly lower cytotoxic killing of allogeneic target cells...
2021: Frontiers in Immunology
Kiyoshi Hirahara, Kota Kokubo, Ami Aoki, Masahiro Kiuchi, Toshinori Nakayama
Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (TEM ) cells, central memory T (TCM ) cells, and tissue-resident memory T (TRM ) cells have been identified. The most recently identified subset, TRM cells, is characterized by the expression of the C-type lectin CD69 and/or the integrin CD103. TRM cells persist locally at sites of mucosal tissue, such as the lung, where they provide frontline defense against various pathogens...
2021: Frontiers in Immunology
Shunsuke Miura, Yusuke Watanabe, Ryosuke Saigusa, Takashi Yamashita, Kouki Nakamura, Megumi Hirabayashi, Takuya Miyagawa, Ayumi Yoshizaki, Maria Trojanowska, Shinichi Sato, Yoshihide Asano
BACKGROUND: Aldehyde dehydrogenase 1 family member A1 (RALDH1)-producing dermal dendritic cells (DCs), a conventional DC subset regulating skin fibrosis, are decreased in the involved skin of patients with systemic sclerosis (SSc). In this study, we investigated the contribution of Fli1 deficiency, a potential predisposing factor of SSc, to the phenotypical alteration of RALDH1-producing dermal DCs by using SSc model mice and SSc skin samples. METHODS: Bleomycin (BLM)-induced skin fibrosis was generated with Fli1+/- and wild-type mice...
May 8, 2021: Arthritis Research & Therapy
Y Sun, P Bao, G Zhang, H Wang, G Wang
OBJECTIVE: To investigate the effect of protein C activator (PCA) from Agkistrodon acutus venom (AAV) in modulating early adaptive immune response of septic rats. OBJECTIVE: Rat models of sepsis were established by intraperitoneal injection of lipopolysaccharide (LPS; 10 mg/kg) in 36 SD rats, which were divided into 6 groups ( n =6) for sample collection at 4, 6, 8, 12, 16 and 24 h after LPS injection, with 6 rats injected with saline as the control group. Another 36 rats were divided into two groups, and 30 min after LPS injection, the rats were treated with SEW2871 (a sphingosine-1-phosphate receptor 1 agonist; 0...
April 20, 2021: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
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