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John A Todd, Marina Evangelou, Antony J Cutler, Marcin L Pekalski, Neil M Walker, Helen E Stevens, Linsey Porter, Deborah J Smyth, Daniel B Rainbow, Ricardo C Ferreira, Laura Esposito, Kara M D Hunter, Kevin Loudon, Kathryn Irons, Jennie H Yang, Charles J M Bell, Helen Schuilenburg, James Heywood, Ben Challis, Sankalpa Neupane, Pamela Clarke, Gillian Coleman, Sarah Dawson, Donna Goymer, Katerina Anselmiova, Jane Kennet, Judy Brown, Sarah L Caddy, Jia Lu, Jane Greatorex, Ian Goodfellow, Chris Wallace, Tim I Tree, Mark Evans, Adrian P Mander, Simon Bond, Linda S Wicker, Frank Waldron-Lynch
BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs...
October 2016: PLoS Medicine
Sylvie Chabot, Fernando Alvarez, Abdelaziz Amrani, Idriss Djilali-Saiah
Identifying the type of diabetogenic CD8(+) T cells that initiate autoimmune diabetes (AID) is a critical step in designing appropriate strategies for the early detection of beta cell-directed autoimmunity and its progression to diabetes. We generated a novel double transgenic (Tg) mouse model on the naturally diabetes resistant C57Bl/6 background, co-expressing two transgenes including a specific TCR anti-lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) carried by CD8(+) T cells and LCMV-NP (as neo-self antigen) expressed by pancreatic beta cells...
August 11, 2016: Autoimmunity
Tom Erkers, Martin Solders, Lotte Verleng, Cecilia Bergström, Arwen Stikvoort, Lalit Rane, Silvia Nava, Olle Ringdén, Helen Kaipe
This study investigated how stromal cells affect the IL-2 pathway in alloantigen-activated T cells. We found that decidual stromal cells (DSCs) from term placentas promoted a high production of IL-2 in cultures with alloantigen-activated T cells. The intensity of expression of cluster of differentiation 25 (CD25; IL-2Rα) on T cells was increased by DSCs, whereas the frequency and intensity of expression of the signaling subunits CD122 (IL-2Rβ) and CD132 (IL-2Rγc) were reduced. Consequently, uptake of IL-2 and STAT5 phosphorylation (pSTAT5) was abrogated...
September 20, 2016: Journal of Leukocyte Biology
Sheikh Fayaz Ahmad, Mushtaq Ahmad Ansari, Ahmed Nadeem, Khairy M A Zoheir, Saleh A Bakheet, Othman A Al-Shabanah, Ammar Cherkess Al Rikabi, Sabry M Attia
Protein tyrosine kinases are key mediators of the signal transduction cascades that control expression of many genes involved in the induction of inflammation caused by arthritis. Here we investigate the effect of the tyrosine kinase inhibitor tyrphostin AG126 on a mouse model of adjuvant-induced arthritis (AIA). We report that when given at 5mg/kg i.p. every 48h from days 0-21, AG126 exerts potent anti-arthritic effects. Further, we investigated the role of AG126 on the key mediators of arthritic inflammation, namely, edema, arthritic score, presence of immunophenotypes including Foxp3(+), CD4(+)Foxp3(+), and CD25(+)Foxp3(+) T regulatory (Treg) cells, as well as pro- and anti-inflammatory mediators...
October 2016: Molecular Immunology
Meixiang Yang, Shasha Chen, Juan Du, Junming He, Yuande Wang, Zehua Li, Guangao Liu, Wanwen Peng, Xiaokang Zeng, Dan Li, Panglian Xu, Wei Guo, Zai Chang, Song Wang, Zhigang Tian, Zhongjun Dong
Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development. Here we show that Tsc1, a repressor of mTOR, is dispensable for the terminal maturation, survival and function of NK cells but is critical to restrict exhaustive proliferation of immature NK cells and activation downstream of IL-15 during NK cell development. Tsc1 is expressed in immature NK cells and is upregulated by IL-15. Haematopoietic-specific deletion of Tsc1 causes a marked decrease in the number of NK cells and compromises rejection of 'missing-self' haematopoietic tumours and allogeneic bone marrow...
2016: Nature Communications
Y S Li, W F He, J Wu
The maturation of dendritic epidermal T lymphocytes (DETCs) in thymus needs ligand-mediated positive selection, and positive selection together with V3γ(+) γδT lymphocytes intrinsic program features order DETCs to specifically migrate to epidermis. Positive selection promotes DETCs to express CD122, which is vital for DETCs to survive and proliferate in skin. DETCs possess memory-like phenotype and are able to rapidly respond to danger signals when they move out from thymus. NKG2D, junctional adhesion molecule-like protein and 2B4 are demonstrated to participate in DETCs activation, except for ligands of T lymphocytes receptor...
January 2016: Zhonghua Shao Shang za Zhi, Zhonghua Shaoshang Zazhi, Chinese Journal of Burns
Pei-Qi Chen, Qian-Ni Liang, Tao-Sheng Huang, Tian-Cai Liu, Ming Li
BACKGROUND: Because of the life-consuming treatment and severe consequences associated with thalassemia, it is more effective to prevent than cure thalassemia. Rapid and sensitive detection is critical for controlling thalassemia. In this study, we developed a rapid and accurate test to genotype nondeletional α- and β-thalassemia mutations by an electrochemical DNA sensor. METHODS: Screen-printed electrodes were used as electrochemical transducers for the sensor, in which the capture probe DNA was attached to the golden surface of the working electrode via an S-Au covalent bond, which is highly suitable for immobilizing the biological element...
September 2016: Journal of Clinical Laboratory Analysis
Jakub Tomala, Marek Kovar
The in vivo biological activity of IL-2 can be dramatically increased by complexing with anti-IL-2 mAb. Moreover, IL-2/anti-IL-2 mAb immunocomplexes selectively stimulate different subsets of immune cells, depending on the clone of anti-IL-2 mAb that is used. Thus, IL-2/S4B6 mAb complexes strongly stimulate CD122(high) populations, namely NK and memory CD8(+) T cells. They also intermediately stimulate Treg cells. Conversely, IL-2/JES6.1 mAb immunocomplexes have no stimulatory activity for CD122(high) populations...
March 2016: Oncoimmunology
T Yamazaki, J M Pitt, M Vétizou, A Marabelle, C Flores, Ø Rekdal, G Kroemer, L Zitvogel
Intratumoral immunotherapies aim at reducing local immunosuppression, as well as reinstating and enhancing systemic anticancer T-cell functions, without inducing side effects. LTX-315 is a first-in-class oncolytic peptide-based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid-derived suppressor cells and by increasing the frequency of polyfunctional T helper type 1/type 1 cytotoxic T cells with a concomitant increase in cytotoxic T-lymphocyte antigen-4 (CTLA4) and drop in PD-1 expression levels...
June 2016: Cell Death and Differentiation
Hongyao Zhang, Ning Li, Jiahui Zhang, Fengjiao Jin, Meihua Shan, Junfang Qin, Yue Wang
In this study, we investigate the effect of miR-34a expression and biological characteristics of breast cancer stem cells (BCSCs). The mammospheres were formed from murine breast cancer cell line 4T1 and regarded as murine BCSCs. Identification of stemness molecules and cloning experiments validate the biological characteristics of BCSCs we have established. We showed that miR-34a, as a tumor suppressor, could separately reduce the stemness of BCSCs and activate the cytotoxic susceptibility of BCSCs to natural killer (NK) cells in vitro via down regulating the expression of Notch1 signaling molecules...
June 2, 2016: Cancer Biology & Therapy
Miguel Muñoz-Ruiz, Julie C Ribot, Ana R Grosso, Natacha Gonçalves-Sousa, Ana Pamplona, Daniel J Pennington, José R Regueiro, Edgar Fernández-Malavé, Bruno Silva-Santos
The mouse thymus produces discrete γδ T cell subsets that make either interferon-γ (IFN-γ) or interleukin 17 (IL-17), but the role of the T cell antigen receptor (TCR) in this developmental process remains controversial. Here we show that Cd3g(+/-) Cd3d(+/-) (CD3 double-haploinsufficient (CD3DH)) mice have reduced TCR expression and signaling strength on γδ T cells. CD3DH mice had normal numbers and phenotypes of αβ thymocyte subsets, but impaired differentiation of fetal Vγ6(+) (but not Vγ4(+)) IL-17-producing γδ T cells and a marked depletion of IFN-γ-producing CD122(+) NK1...
June 2016: Nature Immunology
Peter S Kim, Anna R Kwilas, Wenxin Xu, Sarah Alter, Emily K Jeng, Hing C Wong, Jeffrey Schlom, James W Hodge
Interleukin (IL)-15-N72D superagonist-complexed with IL-15RαSushi-Fc fusion protein (IL-15SA/IL-15RαSu-Fc; ALT-803) has been reported to exhibit significant anti-tumor activity in murine myeloma, rat bladder cancer, and murine glioblastoma models. In this study, we examined the immunomodulatory and anti-tumor effects of IL-15SA/IL-15RαSu-Fc in tumor-free and highly metastatic tumor-bearing mice. Here, IL-15SA/IL-15RαSu-Fc significantly expanded natural killer (NK) and CD8+ T cells. In examining NK cell subsets, the greatest significant increase was in highly cytotoxic and migrating (CD11b+, CD27hi; high effector) NK cells, leading to enhanced function on a per-cell basis...
March 29, 2016: Oncotarget
Kazuyuki Akane, Seiji Kojima, Tak W Mak, Hiroshi Shiku, Haruhiko Suzuki
The Fas/FasL (CD95/CD178) system is required for immune regulation; however, it is unclear in which cells, when, and where Fas/FasL molecules act in the immune system. We found that CD8(+)CD122(+) cells, which are mostly composed of memory T cells in comparison with naïve cells in the CD8(+)CD122(-) population, were previously shown to include cells with regulatory activity and could be separated into CD49d(low) cells and CD49d(high) cells. We established in vitro and in vivo experimental systems to evaluate the regulatory activity of CD122(+) cells...
March 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
Adriana Baz, Penny Groves, Kathy Buttigieg, Simon H Apte, Norbert Kienzle, Anne Kelso
While the functional plasticity of memory CD4(+) T cells has been studied extensively, less is known about this property in memory CD8(+) T cells. Here, we report the direct measurement of plasticity by paired daughter analysis of effector and memory OT-I CD8(+) T cells primed in vivo with ovalbumin. Naïve, effector, and memory OT-I cells were isolated and activated in single-cell culture; then, after the first division, their daughter cells were transferred to new cultures with and without IL-4; expression of IFN-γ and IL-4 mRNAs was measured 5 days later in the resultant subclones...
April 2016: European Journal of Immunology
Yuneivy Cepero-Donates, Volatiana Rakotoarivelo, Marian Mayhue, Averil Ma, Yi-Guang Chen, Sheela Ramanathan
IL-15 is a member of the gamma chain family of cytokines (γc - CD132). The IL-15 receptor (IL-15R) complex consists of 3 subunits: the ligand-binding IL-15Rα chain (CD215), the β chain (CD122; also used by IL-2), and the common γ chain. The biological activities of IL-15 are mostly mediated by the IL-15:IL-15Rα complex, produced by the same cell and 'trans-presented' to responder cells expressing the IL-15Rβγc. The peculiar and almost unique requirement for IL-15 to be trans-presented by IL-15Rα suggests that the biological effects of IL-15 signaling are tightly regulated even at the level of availability of IL-15...
June 2016: Cytokine
Janos Groh, Eliana Ribechini, David Stadler, Tim Schilling, Manfred B Lutz, Rudolf Martini
CLN diseases are mostly fatal lysosomal storage diseases that lead to neurodegeneration in the CNS. We have previously shown that CD8+ T-lymphocytes contribute to axonal perturbation and neuron loss in the CNS of Ppt1(-/-) mice, a model of CLN1 disease. We now investigated the role of the inflammation-related cell adhesion molecule sialoadhesin (Sn) in Ppt1(-/-) and Cln3(-/-) mice, a model of the most frequent form, CLN3 disease. Microglia/macrophages in the CNS of both models showed an upregulation of Sn and markers for proinflammatory M1 polarization and antigen presentation...
May 2016: Glia
Laura K Mackay, Erica Wynne-Jones, David Freestone, Daniel G Pellicci, Lisa A Mielke, Dane M Newman, Asolina Braun, Frederick Masson, Axel Kallies, Gabrielle T Belz, Francis R Carbone
Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed that CD8(+)CD103(+) Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8(+)CD103(+) Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling...
December 15, 2015: Immunity
Lin Cong, Shu-Feng Wang, Zhi-Li Zhao, Rong-Ya Yang
BACKGROUND: Immune responses are somewhat suppressed in immune privileged sites, including the testes, which provide a preexisting opportunity to prolong allograft survival. Previous studies have shown that intratesticular islet allografts enjoy extended survival even without any immunosuppression. However, it is unknown if testicular immune privilege can be exploited to prolong the survival of a solid allograft, including the skin, because it is impractical to implant a solid tissue in human testes...
April 2016: Transplantation
Margarida Lima, Magdalena Leander, Marlene Santos, Ana Helena Santos, Catarina Lau, Maria Luís Queirós, Marta Gonçalves, Sónia Fonseca, João Moura, Maria Dos Anjos Teixeira, Alberto Orfao
Studies of chemokine receptors (CKR) in natural killer- (NK-) cells have already been published, but only a few gave detailed information on its differential expression on blood NK-cell subsets. We report on the expression of the inflammatory and homeostatic CKR on normal blood CD56(+low) CD16(+) and CD56(+high)  CD16(-/+low) NK-cells. Conventional CD56(+low) and CD56(+high) NK-cells present in the normal PB do express CKR for inflammatory cytokines, although with different patterns CD56(+low) NK-cells are mainly CXCR1/CXCR2(+) and CXCR3/CCR5(-/+), whereas mostly CD56(+high) NK-cells are CXCR1/CXCR2(-) and CXCR3/CCR5(+)...
2015: Journal of Immunology Research
Junfeng Liu, Dacan Chen, Golay D Nie, Zhenhua Dai
CD8(+)CD122(+) T-cells have been traditionally described as antigen-specific memory T-cells that respond to previously encountered antigens more quickly and vigorously than their naïve counterparts. However, mounting evidence has demonstrated that murine CD8(+)CD122(+) T-cells exhibit a central memory phenotype (CD44(high)CD62L(high)), regulate T cell homeostasis, and act as regulatory T-cells (Treg) by suppressing both autoimmune and alloimmune responses. Importantly, naturally occurring murine CD8(+)CD122(+) Tregs are more potent in immunosuppression than their CD4(+)CD25(+) counterparts...
2015: Frontiers in Immunology
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