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Sergio Romagnani
The interleukin (IL)-4-induced gene1 (IL4I1), which encodes the L-amino acid oxidase enzyme, plays an important immunoregulatory role. Indeed, this enzyme which is produced by B cells-including neoplastic B cells-dendritic cells and macrophages has been shown to inhibit proliferation, cytotoxicity and IFN-γ production by tumor-infiltrating CD8(+) T cells, thus favoring tumor escape. Moreover, the same gene has been found to be constitutively expressed by CD4(+) T helper 17 (Th17) cells, where it down-regulates cell proliferation through a reduction of CD3 chains expression in the T-cell receptor complex, thus impairing IL-2 production, and by maintaining in the same cells a high expression of Tob1, which inhibits cell cycle entry, through a still unknown mechanism...
October 2016: European Journal of Immunology
Jessica Heinrichs, David Bastian, Anandharaman Veerapathran, Claudio Anasetti, Brain Betts, Xue-Zhong Yu
Graft-versus-host disease (GVHD) is a significant cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Existing strategies to prevent and treat GVHD are incomplete, where a significant portion of allo-HCT recipients developed this complication. Despite this, one such therapy has emerged involving the use of regulatory T cells (Tregs) to control GVHD. The use of natural Tregs (nTregs) yielded positive pre-clinical results and are actively under investigation to reduce GVHD...
2016: J Immunol Res Ther
Diamanda Rigas, Gavin Lewis, Jennifer L Aron, Bowen Wang, Homayon Banie, Ishwarya Sankaranarayanan, Lauriane Galle-Treger, Hadi Maazi, Richard Lo, Gordon J Freeman, Arlene H Sharpe, Pejman Soroosh, Omid Akbari
BACKGROUND: Atopic diseases including asthma exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T cells (Tregs) and the emerging group 2 innate lymphoid cells (ILC2s). While ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. OBJECTIVE: In the present study, we evaluate for the first time how Tregs interact with pulmonary ILC2s and control their function...
October 4, 2016: Journal of Allergy and Clinical Immunology
Magdalena Paterka, Jan Oliver Voss, Johannes Werr, Eva Reuter, Sophia Franck, Tina Leuenberger, Josephine Herz, Helena Radbruch, Tobias Bopp, Volker Siffrin, Frauke Zipp
Counter-balancing regulatory mechanisms, such as the induction of regulatory T cells (Treg), limit the effects of autoimmune attack in neuroinflammation. However, the role of dendritic cells (DCs) as the most powerful antigen-presenting cells, which are intriguing therapeutic targets in this context, is not fully understood. Here, we demonstrate that conditional ablation of DCs during the priming phase of myelin-specific T cells in experimental autoimmune encephalomyelitis (EAE) selectively aborts inducible Treg (iTreg) induction, whereas generation of T helper (Th)1/17 cells is unaltered...
October 2, 2016: Journal of Autoimmunity
Yutaka Kurebayashi, Yukiko Baba, Akiko Minowa, Niken Adiba Nadya, Miyuki Azuma, Akihiko Yoshimura, Shigeo Koyasu, Shigenori Nagai
Transforming growth factor-β (TGF-β) is a pivotal cytokine in the differentiation of regulatory T cells, and Foxo transcription factors positively regulate this process. On the other hand, the function of Foxo transcription factors is negatively regulated by PI3K/Akt signaling, which is activated by TGF-β in many types of cells; yet the role of TGF-β in Akt activity and its downstream substrates in CD4(+) T cells, including Foxo transcription factors, remains to be determined. Herein, we demonstrate that TGF-β selectively induces Akt phosphorylation at Ser473 but not at Thr308 in a class IA PI3K-dependent manner in CD4(+) T cells, resulting in the phosphorylation and inhibition of Foxo transcription factors and negatively regulating the differentiation of induced regulatory T cells (iTregs)...
October 1, 2016: Biochemical and Biophysical Research Communications
Fanny Kryczanowsky, Verena Raker, Edith Graulich, Matthias P Domogalla, Kerstin Steinbrink
Dendritic cells (DCs) are key regulators of protective immune responses and tolerance to (self-)Ags. Therefore, the scientific rationale for the use of tolerogenic DC therapy in the fields of allergies, autoimmunity, and transplantation medicine is strong. In this study, we analyzed the tolerogenic capacity of IL-10-modulated DC (IL-10DC) subpopulations to identify a DC subset that combines potent immunosuppressive activities with valuable immune properties for clinical implementation. IL-10DCs consist of two phenotypically distinct subpopulations: CD83(high)CCR7(+) IL-10DCs and CD83(low)CCR7(-) IL-10DCs...
September 28, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Yogesh Singh, Yuetao Zhou, Xiaolong Shi, Shaqiu Zhang, Anja T Umbach, Madhuri S Salker, Karl S Lang, Florian Lang
CD4+ T helper 9 (Th9) cells are a newly discovered Th cell subset that produce the pleiotropic cytokine IL-9. Th9 cells can protect against tumours and provide resistance against helminth infections. Given their pivotal role in the adaptive immune system, understanding Th9 cell development and the regulation of IL-9 production could open novel immunotherapeutic opportunities. The Na+/H+ exchanger 1 (NHE1) is critically important for regulating intracellular pH (pHi), cell volume, migration and cell survival...
September 14, 2016: Journal of Biological Chemistry
Mitsuhiro Kanamori, Hiroko Nakatsukasa, Masahiro Okada, Qianjin Lu, Akihiko Yoshimura
Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many facets of immune systems. The transcription factor Foxp3 has been characterized as a master regulator of Tregs, and is induced during their thymic development. Foxp3(+) Tregs can also be generated from naïve T cells after stimulation in the presence of TGF-β and IL-2; the resulting cells are called induced Tregs (iTregs) when generated in vitro, or peripheral Tregs (pTregs) when generated in vivo. Compared to tTregs, iTregs have been shown to be unstable, and attempts to generate stable iTregs have been made for clinical applications...
September 9, 2016: Trends in Immunology
Joanna R Ghali, Maliha A Alikhan, Stephen R Holdsworth, A Richard Kitching
Regulatory T (Treg) cells are a suppressive CD4(+) T-cell subset. We generated induced Treg (iTreg) cells and explored their therapeutic potential in a murine model of rapidly progressive glomerulonephritis. Polyclonal naive CD4(+) T cells were cultured in vitro with interleukin-2 (IL-2), transforming growth factor-β1, all-trans-retinoic acid and monoclonal antibodies against interferon-γ and IL-4, generating Foxp3(+) iTreg cells. To enhance their suppressive phenotype, iTreg cultures were modified with the addition of a monoclonal antibody against IL-12p40 or by using RORγt(-/-) CD4(+) T cells...
September 8, 2016: Immunology
Anthony Joetham, Michaela Schedel, Brian P O'Connor, Soohyun Kim, Katsuyuki Takeda, Jordan Abbott, Erwin W Gelfand
BACKGROUND: T regulatory cells attenuate development of asthma in wild-type (WT) mice with both naturally occurring (nTregs) and inducible T regulatory cells (iTregs) exhibiting suppressive activity. When transferred into CD8-deficient (CD8(-/-)) recipients, both cell types enhanced development of allergen-induced airway hyperresponsiveness (AHR). OBJECTIVE: To determine if the pathways leading to enhancement of lung allergic responses by transferred nTregs and iTregs differed...
August 16, 2016: Journal of Allergy and Clinical Immunology
Yuetao Zhou, Madhuri S Salker, Britta Walker, Patrick Münzer, Oliver Borst, Meinrad Gawaz, Erich Gulbins, Yogesh Singh, Florian Lang
BACKGROUND/AIMS: Regulatory T cell (Treg) is required for the maintenance of tolerance to various tissue antigens and to protect the host from autoimmune disorders. However, Treg may, indirectly, support cancer progression and bacterial infections. Therefore, a balance of Treg function is pivotal for adequate immune responses. Acid sphingomyelinase (ASM) is a rate limiting enzyme involved in the production of ceramide by breaking down sphingomyelin. Previous studies in T-cells have suggested that ASM is involved in CD28 signalling, T lymphocyte granule secretion, degranulation, and vesicle shedding similar to the formation of phosphatidylserine-exposing microparticles from glial cells...
2016: Cellular Physiology and Biochemistry
Bruce M Hall
In the 1970s the capacity of T cells to inhibit immunity and those from transplant tolerant hosts to transfer alloantigen-specific suppression to lymphopenic recipients was described. CD4T suppressor cells that ex vivo reverted to effector cells were described in the 1980s. Their antigen-specific suppressor function could be preserved by stimulation by specific donor alloantigen and cytokines from activated lymphocytes. This led to the finding that alloantigen-specific T suppressor cells express IL-2 receptor (CD25) and that IL-2 in part promotes their survival...
August 5, 2016: Transplantation
Ludovic Belle, Kimberle Agle, Vivian Zhou, Cheng Yin-Yuan, Richard Komorowski, Daniel Eastwood, Brent Logan, Jie Sun, Nico Ghilardi, Daniel Cua, Calvin B Williams, Melanie Gaignage, Reece Marillier, Jacques van Snick, William R Drobyski
Re-establishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft versus host disease (GVHD), and re-calibrate the effector and regulatory arms of the immune system. However, clinically feasible, cost effective strategies that do not require extensive ex vivo cellular manipulation have remained elusive. In the current study, we demonstrate that inhibition of the interleukin 27p28 (IL-27p28) signaling pathway through antibody blockade or genetic ablation prevented lethal GVHD in multiple murine transplant models...
August 3, 2016: Blood
Amir Hossein Massoud, Louis-Marie Charbonnier, David Lopez, Matteo Pellegrini, Wanda Phipatanakul, Talal A Chatila
Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the gene encoding the interleukin (IL)-4 receptor alpha chain (Il4ra(R576)) promotes conversion of induced Treg (iTreg) cells toward a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4Rα(R576) of the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway that involves extracellular-signal-regulated kinase, IL-6 and the transcription factor STAT3...
September 2016: Nature Medicine
Lena Wyss, Brian D Stadinski, Carolyn G King, Sonja Schallenberg, Nicholas I McCarthy, Jun Young Lee, Karsten Kretschmer, Luigi M Terracciano, Graham Anderson, Charles D Surh, Eric S Huseby, Ed Palmer
The manner in which regulatory T cells (Treg cells) control lymphocyte homeostasis is not fully understood. We identified two Treg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD-1(lo)CD25(lo) (Triple(lo)) Treg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) Tconv cells into induced Treg cells (iTreg cells)...
September 2016: Nature Immunology
Jessica Heinrichs, Jun Li, Hung Nguyen, Yongxia Wu, David Bastian, Anusara Daethanasanmak, M-Hanief Sofi, Steven Schutt, Chen Liu, Junfei Jin, Brian Betts, Claudio Anasetti, Xue-Zhong Yu
Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (Allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemia (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4(+) or CD8(+) T cells and tested their ability to suppress GVH and maintain GVL responses...
June 2016: Oncoimmunology
Il-Kyu Kim, Yeonseok Chung, Chang-Yuil Kang
TH9 cells have been implicated in triggering antitumor immunity. We have identified that GITR co-stimulation inhibits iTreg cell generation but drives TH9 cell differentiation, thereby suppressing tumor growth via enhancing the function of DCs and CTLs in vivo. Our findings provide novel mechanisms by which GITR agonists exert antitumor activity.
May 2016: Oncoimmunology
Kiyohiko Hotta, Akihiro Aoyama, Tetsu Oura, Yohei Yamada, Makoto Tonsho, Kyu Ha Huh, Kento Kawai, David Schoenfeld, James S Allan, Joren C Madsen, Gilles Benichou, Rex-Neal Smith, Robert B Colvin, David H Sachs, A Benedict Cosimi, Tatsuo Kawai
Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen...
July 7, 2016: JCI Insight
M Jargosch, S Kröger, E Gralinska, U Klotz, Z Fang, W Chen, U Leser, J Selbig, D Groth, R Baumgrass
Data integration has become a useful strategy for uncovering new insights into complex biological networks. We studied whether this approach can help to delineate the signal transducer and activator of transcription 6 (STAT6)-mediated transcriptional network driving T helper (Th) 2 cell fate decisions. To this end, we performed an integrative analysis of publicly available RNA-seq data of Stat6-knockout mouse studies together with STAT6 ChIP-seq data and our own gene expression time series data during Th2 cell differentiation...
2016: Genetics and Molecular Research: GMR
Maryam Azimi, Saeed Aslani, Sahar Mortezagholi, Amir Salek, Mohammad Reza Javan, Alireza Rezaiemanesh, Mojgan Ghaedi, Mehrdad Gholamzad, Eisa Salehi
Two categories of regulatory T cells (Tregs), nTreg and iTreg, play vital roles in orchestrating the integrity of a host in the course of an immune response. Tregs commonly belong to CD4+ CD25+ T cells and they are characterized by a transcription factor - forkhead box P3 (FoxP3). Within the space of the last few years, interests have been drawn to Tregs as a therapeutic tool in several settings like autoimmune disease, transplantation, and tumor disorders. As a consequence, to assess the functional properties of Tregs, namely through their ability to suppress other cells, cytokine expression, and proliferation in a variety of conditions, it is mandatory to gain better approaches to this end...
October 2016: Immunological Investigations
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