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https://www.readbyqxmd.com/read/28077684/targeting-aurora-kinase-a-and-jak2-prevents-gvhd-while-maintaining-treg-and-antitumor-ctl-function
#1
Brian C Betts, Anandharaman Veerapathran, Joseph Pidala, Hua Yang, Pedro Horna, Kelly Walton, Christopher L Cubitt, Steven Gunawan, Harshani R Lawrence, Nicholas J Lawrence, Said M Sebti, Claudio Anasetti
Graft-versus-host disease (GVHD) is a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation. T cell costimulation by CD28 contributes to GVHD, but prevention is incomplete when targeting CD28, downstream mammalian target of rapamycin (mTOR), or Aurora A. Likewise, interleukin-6 (IL-6)-mediated Janus kinase 2 (JAK2) signaling promotes alloreactivity, yet JAK2 inhibition does not eliminate GVHD. We provide evidence that blocking Aurora A and JAK2 in human T cells is synergistic in vitro, prevents xenogeneic GVHD, and maintains antitumor responses by cytotoxic T lymphocytes (CTLs)...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28060341/in-vitro-differentiation-of-human-cd4-foxp3-induced-regulatory-t-cells-itregs-from-na%C3%A3-ve-cd4-t-cells-using-a-tgf-%C3%AE-containing-protocol
#2
Angelika Schmidt, Szabolcs Éliás, Rubin N Joshi, Jesper Tegnér
Regulatory T cells (Tregs) are an integral part of peripheral tolerance, suppressing immune reactions against self-structures and thus preventing autoimmune diseases. Clinical approaches to adoptively transfer Tregs, or to deplete Tregs in cancer, are underway with promising first outcomes. Because the number of naturally occurring Tregs (nTregs) is very limited, studying certain Treg features using in vitro induced Tregs (iTregs) can be advantageous. To date, the best although not absolutely specific protein marker to delineate Tregs is the transcription factor FOXP3...
December 30, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28059703/glycolysis-and-glutaminolysis-cooperatively-control-t-cell-function-by-limiting-metabolite-supply-to-n-glycosylation
#3
Lindsey Araujo, Phillip Khim, Haik Mkhikian, Christie-Lynn Mortales, Michael Demetriou
Rapidly proliferating cells switch from oxidative phosphorylation to aerobic glycolysis plus glutaminolysis, markedly increasing glucose and glutamine catabolism. Although Otto Warburg first described aerobic glycolysis in cancer cells >90 years ago, the primary purpose of this metabolic switch remains controversial. The hexosamine biosynthetic pathway requires glucose and glutamine for de novo synthesis of UDP-GlcNAc, a sugar-nucleotide that inhibits receptor endocytosis and signaling by promoting N-acetylglucosamine branching of Asn (N)-linked glycans...
January 6, 2017: ELife
https://www.readbyqxmd.com/read/27919837/ex-vivo-itreg-differentiation-revisited-convenient-alternatives-to-existing-strategies
#4
Billur Akkaya, Amanda H Holstein, Christopher Isaac, Mitra P Maz, Deborah D Glass, Ethan M Shevach, Munir Akkaya
Ex-vivo differentiation of regulatory T cells (Tregs) from naïve CD4(+) T-cells has been widely used in immunological research. Isolation of a highly pure naïve T cell population is the key factor that determines the efficiency of subsequent Treg differentiation. Currently, this step relies mostly on FACS sorting, which is often costly, time consuming, and inconvenient. Alternatively, magnetic separation of T-cells can be performed; yet, available protocols fail to reach sort level purity and consequently result in low Treg differentiation efficiency...
December 2, 2016: Journal of Immunological Methods
https://www.readbyqxmd.com/read/27896636/tnf-superfamily-cytokines-in-the-promotion-of-th9-differentiation-and-immunopathology
#5
REVIEW
Françoise Meylan, Richard M Siegel
The tumor necrosis factor (TNF) receptors and their corresponding cytokine ligands have been implicated in many aspects of the biology of immune functions. TNF receptors have key roles during various stages of T cell homeostasis. Many of them can co-stimulate lymphocyte proliferation and cytokine production. Additionally, several TNF cytokines can regulate T cell differentiation, including promoting Th1, Th2, Th17, and more recently the newly described Th9 subset. Four TNF family cytokines have been identified as regulators for IL-9 production by T cells...
November 28, 2016: Seminars in Immunopathology
https://www.readbyqxmd.com/read/27861285/cd4-cd25-t-regulatory-cells-in-transplantation-tolerance-25-years-on
#6
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. CD4 T 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...
December 2016: Transplantation
https://www.readbyqxmd.com/read/27806875/immune-regulatory-effects-of-high-dose-vitamin-d3-supplementation-in-a-randomized-controlled-trial-in-relapsing-remitting-multiple-sclerosis-patients-receiving-ifn%C3%AE-the-solarium-study
#7
Anne-Hilde Muris, Joost Smolders, Linda Rolf, Marielle Thewissen, Raymond Hupperts, Jan Damoiseaux
Multiple sclerosis (MS) is characterized by a disturbed immune homeostasis and low serum vitamin D levels are associated with an increased disease activity. While vitamin D has been hypothesized to promote the maintenance of immune homeostasis, vitamin D supplementation could be of benefit to patients with MS. The SOLAR study investigated the effects of high dose vitamin D3 supplementation on clinical outcomes in a randomized controlled trial. Here we present the immune regulatory effects, investigated in the SOLARIUM sub-study...
November 15, 2016: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/27726138/il4i1-key-immunoregulator-at-a-crossroads-of-divergent-t-cell-functions
#8
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
https://www.readbyqxmd.com/read/27722210/regulatory-t-cell-therapy-for-graft-versus-host-disease
#9
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: Journal of Immunology Research and Therapy
https://www.readbyqxmd.com/read/27717665/type-2-innate-lymphoid-cell-suppression-by-regulatory-t%C3%A2-cells-attenuates-airway-hyperreactivity-and-requires-inducible-t-cell-costimulator-inducible-t-cell-costimulator-ligand
#10
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 (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. OBJECTIVE: In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function...
October 4, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27707650/dendritic-cells-tip-the-balance-towards-induction-of-regulatory-t-cells-upon-priming-in-experimental-autoimmune-encephalomyelitis
#11
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...
January 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/27697523/tgf-%C3%AE-induced-phosphorylation-of-akt-and-foxo-transcription-factors-negatively-regulates-induced-regulatory-t-cell-differentiation
#12
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
https://www.readbyqxmd.com/read/27683749/il-10-modulated-human-dendritic-cells-for-clinical-use-identification-of-a-stable-and-migratory-subset-with-improved-tolerogenic-activity
#13
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
https://www.readbyqxmd.com/read/27629415/alkaline-cytosolic-ph-and-high-sodium-hydrogen-exchanger-1-nhe1-activity-in-th9-cells
#14
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 tumors 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; gene name Slc9α1)) is critically important for regulating intracellular pH (pHi), cell volume, migration, and cell survival...
November 4, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27623114/induced-regulatory-t-cells-their-development-stability-and-applications
#15
REVIEW
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...
November 2016: Trends in Immunology
https://www.readbyqxmd.com/read/27606831/induced-regulatory-t-cells-are-phenotypically-unstable-and-do-not-protect-mice-from-rapidly-progressive-glomerulonephritis
#16
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...
January 2017: Immunology
https://www.readbyqxmd.com/read/27542981/inducible-and-naturally-occurring-t-regulatory-cells-enhance-lung-allergic-responses-via-divergent-transcriptional-pathways
#17
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
https://www.readbyqxmd.com/read/27512981/acid-sphingomyelinase-asm-is-a-negative-regulator-of-regulatory-t-cell-treg-development
#18
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
https://www.readbyqxmd.com/read/27495750/cd4-cd25-t-regulatory-cells-in-transplantation-tolerance-25-years-on
#19
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
https://www.readbyqxmd.com/read/27488350/blockade-of-interleukin-27-signaling-reduces-gvhd-in-mice-by-augmenting-treg-reconstitution-and-stabilizing-foxp3-expression
#20
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
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