Propagation of Mouse and Human T Cells with Defined Antigen Specificity and Function

2007 ◽  
pp. 179-197 ◽  
Author(s):  
Peter A. Cohen ◽  
Daniel H. Fowler ◽  
Hyun Kim ◽  
Richard L. White ◽  
Brian J. Czerniecki ◽  
...  
Keyword(s):  
T Cells ◽  
Antigen Specificity ◽  
Human T Cells ◽  
And Function

Role of alanyl aminopeptidase in growth and function of human T cells (review).

1999 ◽  
Author(s):  
U Lendeckel ◽  
M Arndt ◽  
K Frank ◽  
T Wex ◽  
S Ansorge
Keyword(s):  
T Cells ◽  
Human T Cells ◽  
And Function ◽  
Alanyl Aminopeptidase

CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase

2018 ◽  
Vol 399 (10) ◽  
pp. 1175-1182 ◽  
Author(s):  
Jürgen Schneider-Schaulies ◽  
Niklas Beyersdorf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cells ◽  
Tricyclic Antidepressant ◽  
Acid Sphingomyelinase ◽  
Human T Cells ◽  
And Function ◽  
Rate Limiting ◽  
Deficient Mice

AbstractAcid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+Foxp3+regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4+T (Tconv) cells. In ASM-deficient (Smpd1−/−) as compared to wt mice, membranes of T cells contain 7–10-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4+T cells in ASM-deficient mice and their suppressive activityin vitroare increased. Moreover,in vitrostimulation of ASM-deficient T cells in the presence of TGF-β and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4+T cells within a few days. This fast alteration of the balance between T cell populationsin vitrois due to the elevated cell death of Tconv cells and protection of the CD25highTreg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.

scholarly journals TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

2012 ◽  
Vol 189 (9) ◽  
pp. 4510-4519 ◽  
Author(s):  
Anna Pasetto ◽  
Lars Frelin ◽  
Soo Aleman ◽  
Fredrik Holmström ◽  
Anette Brass ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Replication ◽  
Antigen Specificity ◽  
Functional Avidity ◽  
Human T Cells

LMP2-Specific TCR Gene Therapy for Hodgkin Lymphoma - Design of a Dominant TCR Construct for Immunotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2762-2762
Author(s):  
Daniel P. Hart ◽  
Sharyn Thomas ◽  
Shao-an Xue ◽  
Emma C. Morris ◽  
Hans J. Stauss
Keyword(s):  
T Cells ◽  
Cell Surface ◽  
Hodgkin Lymphoma ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Beta Chain ◽  
Antigen Specificity ◽  
Human T Cells ◽  
Beta Chain Genes ◽  
Tcr Gene Therapy

Abstract Hodgkin lymphoma (HL) is the second most commonly diagnosed cancer in the 15–29 year old population. EBV-positive Hodgkin lymphoma typically demonstrates latency II antigen expression, characterised by loss of most EBV antigens except for the latent membrane protein (LMP) 1 and 2 and the EBNA-1 protein. LMP2 is expressed in Reed Sternberg cells and may serve as a target for antigen-specific immunotherapy. However, LMP2 is poorly immunogenic and it is often difficult to generate autologous LMP2-specific cytotoxic T lymphocytes (CTL) for adoptive immunotherapy. T cell receptor (TCR) gene transfer using retroviral vectors containing the TCR alpha and beta chain genes can reproducibly redirect the antigen specificity of a given population of T cells. Such an approach has been used here to generate LMP2-specific CTL independent of the immuno-competence of the patient. The goal of this study was to generate a retroviral TCR construct suitable for rapid and efficient production of LMP2-specific CTL. Retrovirally introduced TCRs compete with endogenous TCRs for a limited pool of CD3 molecules required for assembly of the TCR complex. Competition for CD3 molecules may limit surface expression of the introduced TCR resulting in a transduced T cell with poor functional avidity. In an attempt to generate a ‘highly competitive’ LMP2-TCR the following modifications were made to the retroviral vector construct: nucleotide sequences were codon optimised for efficient translation in human cells; the TCR chain constant regions were altered to contain murine sequences to enhance CD3 binding; and the TCR alpha and beta chain genes were linked by a self-cleaving 2A sequence from the porcine teschovirus to enhance equimolar expression of both TCR chains. The unmodified HLA-A2-restricted LMP2-specific TCR was poorly expressed in primary human T cells, suggesting that it competed inefficiently with endogenous TCR chains for cell surface expression. Very few CD8+Vβ13+ T cells were detectable after LMP2-TCR transduction (up to 2.5% of viable CD3+ T cells, as detected by FACs analysis using monoclonal anti-Vβ13 antibodies), which included 1.9% CD8+ T cells expressing endogenous Vβ13+ TCRs as quantified in mock-transduced control cells. Poor expression of the wild type LMP2-TCR was consistently observed in independent transduction experiments. However, transduction with the modified LMP2-TCR construct resulted in cell surface expression of the TCR in 55–65% viable CD3+ T cells. HLA-A2/LMP2 pentamer binding was demonstrated in 36–39% CD8+ CTL cells immediately post transduction. The transduced cells showed peptide-specific IFNγ and IL2 production and killed target cells displaying the LMP2 peptide. Of major importance, expression of the introduced LMP2-TCR completely suppressed the cell surface expression of almost the entire repertoire of endogenous TCR combinations, including ‘mis-paired’ TCRs in the transduced primary human T cells. ‘Mis-paired’ TCRs contain an introduced alpha chain paired with an endogenous beta chain and vice versa. The antigen specificity of such mispaired TCRs generated after transduction is unknown and could lead to unwanted side effects. The design of vectors containing modified TCR sequences, which produce ‘dominant’ TCRs may improve the efficacy of TCR gene therapy and reduce the risk of potential auto-reactivity of endogenous and ‘mis-paired’ TCR combinations. We have shown that LMP2-specific T cells can be readily generated by TCR gene transfer with minimal risk of autoreactivity.

scholarly journals Expansion of Functional Regulatory T Cells Using Soluble RAGE Prevents Type 1 Diabetes

2020 ◽  
Author(s):  
Sherman S. Leung ◽  
Danielle J. Borg ◽  
Domenica A. McCarthy ◽  
Tamar E. Boursalian ◽  
Justen Cracraft ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Soluble Rage ◽  
Human T Cells ◽  
Glycation End Products ◽  
Term Administration ◽  
Pancreatic Lymph Nodes ◽  
And Function

AbstractType 1 diabetes (T1D) is an autoimmune disease with no cure. Therapeutic translation has been hampered by preclinical reproducibility. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent centers. Treatment with sRAGE increased regulatory T cells (Tregs) within islets, pancreatic lymph nodes and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE using knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy at multiple research centers and in human T cells.

Engineering the fate and function of human T-cells via 3D bioprinting

2020 ◽  
Author(s):  
Zhizhong Jin ◽  
Xinda Li ◽  
Xinzhi Zhang ◽  
Desousa Paul ◽  
Tao Xu ◽  
...  
Keyword(s):  
T Cells ◽  
3D Bioprinting ◽  
Human T Cells ◽  
And Function

Expression and function of the B and T lymphocyte attenuator (BTLA/CD272) on human T cells

2006 ◽  
Vol 344 (4) ◽  
pp. 1121-1127 ◽  
Author(s):  
Noriko Otsuki ◽  
Yousuke Kamimura ◽  
Masaaki Hashiguchi ◽  
Miyuki Azuma
Keyword(s):  
T Cells ◽  
T Lymphocyte ◽  
Human T Cells ◽  
And Function

Adoptive Transfer of T Cells for Therapy of Disseminated Leukemia: Antigen Specificity And Function of Tumor-Reactive T Cells

2018 ◽  
pp. 199-218
Author(s):  
Jay P. Klarnet ◽  
Donald E. Kern ◽  
Kiyotaka Okuno ◽  
Martin A. Cheever ◽  
Philip D. Greenberg
Keyword(s):  
T Cells ◽  
Adoptive Transfer ◽  
Antigen Specificity ◽  
And Function ◽  
Leukemia Antigen

scholarly journals Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 575-584 ◽  
Author(s):  
Manik C. Ghosh ◽  
Dolgor Baatar ◽  
Gary Collins ◽  
Arnell Carter ◽  
Fred Indig ◽  
...  
Keyword(s):  
T Cells ◽  
Actin Polymerization ◽  
Cell Types ◽  
Cell Surface Receptor ◽  
Kinase Activation ◽  
Disease States ◽  
Chemokine Signaling ◽  
Human T Cells ◽  
Surface Receptor ◽  
And Function

Abstract Dexamethasone (DM) is a synthetic member of the glucocorticoid (GC) class of hormones that possesses anti-inflammatory and immunosuppressant activity and is commonly used to treat chronic inflammatory disorders, severe allergies, and other disease states. Although GCs are known to mediate well-defined transcriptional effects via GC receptors (GCR), there is increasing evidence that GCs also initiate rapid nongenomic signaling events in a variety of cell types. Here, we report that DM induces the phosphorylation of Lck and the activation of other downstream mediators, including p59Fyn, Zap70, Rac1, and Vav in resting but not activated human T cells. DM treatment also augments CXCL12-mediated signaling in resting T cells through its cell surface receptor, CXCR4 resulting in the enhanced actin polymerization, Rac activation, and cell migration on ligand exposure. Lck was found to be a critical intermediate in these DM-induced signaling activities. Moreover, DM-mediated Lck phosphorylation in T cells was dependent on the presence of both the GCR and the CD45 molecule. Overall, these results elucidate additional nongenomic effects of DM and the GCR on resting human T cells, inducing Lck and downstream kinase activation and augmenting chemokine signaling and function.

scholarly journals A novel self-lipid antigen targets human T cells against CD1c+ leukemias

2014 ◽  
Vol 211 (7) ◽  
pp. 1363-1377 ◽  
Author(s):  
Marco Lepore ◽  
Claudia de Lalla ◽  
S. Ramanjaneyulu Gundimeda ◽  
Heiko Gsellinger ◽  
Michela Consonni ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Leukemia ◽  
Immune Surveillance ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Antigen Specificity ◽  
Immunodeficient Mice ◽  
Human T Cells ◽  
Lipid Antigen

T cells that recognize self-lipids presented by CD1c are frequent in the peripheral blood of healthy individuals and kill transformed hematopoietic cells, but little is known about their antigen specificity and potential antileukemia effects. We report that CD1c self-reactive T cells recognize a novel class of self-lipids, identified as methyl-lysophosphatidic acids (mLPAs), which are accumulated in leukemia cells. Primary acute myeloid and B cell acute leukemia blasts express CD1 molecules. mLPA-specific T cells efficiently kill CD1c+ acute leukemia cells, poorly recognize nontransformed CD1c-expressing cells, and protect immunodeficient mice against CD1c+ human leukemia cells. The identification of immunogenic self-lipid antigens accumulated in leukemia cells and the observed leukemia control by lipid-specific T cells in vivo provide a new conceptual framework for leukemia immune surveillance and possible immunotherapy.

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