scholarly journals Immunosuppression byN-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

2013 ◽  
Vol 34 (5) ◽  
pp. 820-831 ◽  
Author(s):  
Sascha Kahlfuß ◽  
Narasimhulu Simma ◽  
Judith Mankiewicz ◽  
Tanima Bose ◽  
Theresa Lowinus ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neuronal Development ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Effector Cells ◽  
Ifn Γ

N-Methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimer's disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drug's effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells toward chemokines. These activities correlated with a reduction in T-cell receptor (TCR)-induced Ca2+mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less interleukin-2 (IL-2) and gamma interferon (IFN-γ), whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knockout mice, the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of Kv1.3 and KCa3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that Kv1.3 and KCa3.1 channels are their major effectors.

scholarly journals Differential Expression of Interleukin-2 and Gamma Interferon in Human Immunodeficiency Virus Disease

2001 ◽  
Vol 75 (20) ◽  
pp. 9983-9985 ◽  
Author(s):  
Scott F. Sieg ◽  
Douglas A. Bazdar ◽  
Clifford V. Harding ◽  
Michael M. Lederman
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Virus Disease ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Gamma Interferon ◽  
Immunodeficiency Virus ◽  
Ifn Γ

ABSTRACT Subnormal T-cell production of interleukin-2 (IL-2) in human immunodeficiency virus (HIV) disease has been described; however, it is not clear whether failure to synthesize IL-2 represents a selective or global defect in T-cell cytokine production. We evaluated the intracellular production of gamma interferon (IFN-γ) and IL-2 in CD4+ cells that were stimulated with staphylococcal enterotoxin B or cytomegalovirus antigen. Strikingly, IFN-γ and IL-2 are differentially regulated in T cells of HIV-infected patients such that the numbers of CD69+ cells or IFN-γ-positive cells that make IL-2 are proportionally decreased in CD4+ T cells from HIV-infected patients. These findings demonstrate a selective defect in IL-2 production and suggest that enumeration of IFN-γ-producing cells in response to T-cell receptor stimulation, while providing some estimate of antigen-reactive cell frequency, may not reflect or predict “normal” T-cell function in HIV-infected patients.

scholarly journals Low Levels of NF-κB/p65 Mark Anergic CD4+T Cells and Correlate with Disease Severity in Sarcoidosis

2010 ◽  
Vol 18 (2) ◽  
pp. 223-234 ◽  
Author(s):  
Nam-Sihk Lee ◽  
Laura Barber ◽  
Ali Kanchwala ◽  
Carter J. H. Childs ◽  
Yash P. Kataria ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Protein Levels ◽  
T Cell Anergy ◽  
Ifn Γ ◽  
Low Levels ◽  
Stimulation Of

ABSTRACTT lymphocytes from patients with sarcoidosis respond weakly when stimulated with mitogen or antigen. However, the mechanisms responsible for this anergy are not fully understood. Here, we investigated the protein levels of nuclear transcription factor NF-κB (p50, p65, and p105), IκBα (inhibitor of NF-κB), T-cell receptor (TCR) CD3ζ-chain, tyrosine kinase p56LCK, and nuclear factor of activated T cells c2 (NF-ATc2) in peripheral blood CD4+T cells from patients with sarcoidosis. Baseline expression of p65 in these lymphocytes was reduced in 50% of patients. The reduced levels of p65 in sarcoid CD4+T cells concurred with decreased levels of p50, p105, CD3ζ, p56LCK, IκBα, and NF-ATc2. Polyclonal stimulation of NF-κB-deficient sarcoid T cells resulted in reduced expression of CD69 and CD154, decreased proliferation, and cytokine (i.e., interleukin 2 [IL-2] and gamma interferon [IFN-γ]) production. The clinical significance of these findings is suggested by the association between low p65 levels and the development of more severe and active sarcoidosis. Although correlative, our results support a model in which multiple intrinsic signaling defects contribute to peripheral T-cell anergy and the persistence of chronic inflammation in sarcoidosis.

scholarly journals Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4

2005 ◽  
Vol 25 (10) ◽  
pp. 4117-4128 ◽  
Author(s):  
Tara J. Dillon ◽  
Kendall D. Carey ◽  
Scott A. Wetzel ◽  
David C. Parker ◽  
Philip J. S. Stork
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Cell Function ◽  
Costimulatory Molecule ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
T Cell Function

ABSTRACT The mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) is activated following engagement of the T-cell receptor and is required for interleukin 2 (IL-2) production and T-cell proliferation. This activation is enhanced by stimulation of the coreceptor CD28 and inhibited by the coreceptor CTLA-4. We show that the small G protein Rap1 is regulated in the opposite manner; it is inhibited by CD28 and activated by CTLA-4. Together, CD3 and CTLA-4 activate Rap1 in a sustained manner. To delineate T-cell function in the absence of Rap1 activity, we generated transgenic mice expressing Rap1GAP1, a Rap1-specific GTPase-activating protein. Transgenic mice showed lymphadenopathy, and transgenic T cells displayed increased ERK activation, proliferation, and IL-2 production. More significantly, the inhibitory effect of CTLA-4 on T-cell function in Rap1GAP1-transgenic T cells was reduced. We demonstrate that CTLA-4 activates Rap1, and we propose that intracellular signals from CTLA-4 antagonize CD28, at least in part, at the level of Rap1.

scholarly journals Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor–mediated p38α activation and impairs interferon-γ production

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2229-2237 ◽  
Author(s):  
Ludmila Jirmanova ◽  
Dandapantula N. Sarma ◽  
Dragana Jankovic ◽  
Paul R. Mittelstadt ◽  
Jonathan D. Ashwell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Function ◽  
Alternative Pathway ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Wild Type ◽  
T Helper 1 ◽  
Ifn Γ

AbstractT cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38α and β on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38α knockin mice in which Tyr323 was replaced with Phe (p38αY323F). TCR-mediated stimulation failed to activate p38αY323F as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38α catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38αY323F T cells, which also produced less interferon (IFN)–γ than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38αY323F mice immunized with T-helper 1 (Th1)–inducing antigens generated normal Th1 effector cells, but these cells produced less IFN-γ than wild-type cells when stimulated through the TCR. Thus, the Tyr323-dependent pathway and not the classic mitogen-activated protein (MAP) kinase cascade is the physiologic means of p38α activation through the TCR and is necessary for normal Th1 function but not Th1 generation.

scholarly journals In Vivo Priming of Cd4 T Cells That Produce Interleukin (Il)-2 but Not IL-4 or Interferon (Ifn)-γ, and Can Subsequently Differentiate into IL-4–Or IFN-γ–Secreting Cells

2001 ◽  
Vol 194 (8) ◽  
pp. 1069-1080 ◽  
Author(s):  
Xiaowen Wang ◽  
Tim Mosmann
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Effector Cells ◽  
Ifn Γ

The differentiation of antigen-stimulated naive CD4 T cells into T helper (Th)1 or Th2 effector cells can be prevented in vitro by transforming growth factor (TGF)-β and anti–interferon (IFN)-γ. These cells proliferate and synthesize interleukin (IL)-2 but not IFN-γ or IL-4, and can differentiate into either Th1 or Th2 cells. We have now used two-color Elispots to reveal substantial numbers of primed cells producing IL-2 but not IL-4 or IFN-γ during the Th1- or Th2-biased immune responses induced by soluble proteins or with adjuvants. These cells were CD4+CD44high and were present during immediate and long-term immune responses of normal mice. Naive T cell receptor for antigen (TCR) transgenic (DO11.10) T cells were primed in vivo after adoptive transfer into normal hosts and FACS® cloned under conditions that did not allow further differentiation. After clonal proliferation, aliquots of each clone were cultured in Th1- or Th2-inducing conditions. Many in vivo–primed cells were uncommitted, secreting IL-2 but not IL-4 or IFN-γ at the first cloning step, but secreting either IL-4 or IFN-γ after differentiation in the appropriate conditions. These in vivo-primed, uncommitted, IL-2–producing cells may constitute an expanded pool of antigen-specific cells that provide extra flexibility for immune responses by differentiating into Th1 or Th2 phenotypes later during the same or subsequent immune responses.

scholarly journals Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

2019 ◽  
Vol 21 (1) ◽  
pp. 68 ◽  
Author(s):  
Maissa Mhibik ◽  
Adrian Wiestner ◽  
Clare Sun
Keyword(s):  
T Cells ◽  
T Cell ◽  
Kinase Inhibitors ◽  
Synapse Formation ◽  
Cell Function ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Compartment ◽  
Bcr Signaling

B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.

scholarly journals Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy

2019 ◽  
Vol 11 (496) ◽  
pp. eaav5989 ◽  
Author(s):  
Christina Claus ◽  
Claudia Ferrara ◽  
Wei Xu ◽  
Johannes Sam ◽  
Sabine Lang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Antigen ◽  
Human Tumor ◽  
Tumor Stroma ◽  
Cell Receptor ◽  
Effector Cells ◽  
Receptor Signal ◽  
Ifn Γ ◽  
Tumor Remission

Endogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti–4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency on Fcγ receptor–mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP–4-1BBL (RG7826) and CD19–4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen–mediated hyperclustering without systemic activation by FcγR binding. We could show targeting of FAP–4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer–bearing rhesus monkey. Combination of FAP–4-1BBL with tumor antigen–targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-γ and granzyme B secretion. Further, combination of FAP– or CD19–4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8+T cells. FAP– and CD19–4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies.

scholarly journals DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haiyan Zhou ◽  
Xinyi Peng ◽  
Jie Hu ◽  
Liwen Wang ◽  
Hairong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Whole Body ◽  
Brown Adipose ◽  
Ifn Γ ◽  
Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Michael R. Verneris ◽  
Mobin Karami ◽  
Jeanette Baker ◽  
Anishka Jayaswal ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Malignant Cell ◽  
Leukemic Cells ◽  
Target Cells ◽  
High Dose ◽  
Effector Cells ◽  
Nkg2d Expression

Abstract Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072)

scholarly journals CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help.

1993 ◽  
Vol 177 (6) ◽  
pp. 1791-1796 ◽  
Author(s):  
F A Harding ◽  
J P Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Histocompatibility Complex ◽  
Necessary And Sufficient ◽  
Additional Antigen

The activation requirements for the generation of CD8+ cytotoxic T cells (CTL) are poorly understood. Here we demonstrate that in the absence of exogenous help, a CD28-B7 interaction is necessary and sufficient for generation of class I major histocompatibility complex-specific CTL. Costimulation is required only during the inductive phase of the response, and not during the effector phase. Transfection of the CD28 counter receptor, B7, into nonstimulatory P815 cells confers the ability to elicit P815-specific CTL, and this response can be inhibited by anti-CD28 Fab or by the chimeric B7-binding protein CTLA4Ig. Anti-CD28 monoclonal antibody (mAb) can provide a costimulatory signal to CD8+ T cells when the costimulatory capacity of splenic stimulators is destroyed by chemical fixation. CD28-mediated signaling provokes the release of interleukin 2 (IL-2) from the CD8+ CTL precursors, as anti-CD28 mAb could be substituted for by the addition of IL-2, and an anti-IL-2 mAb can block the generation of anti-CD28-induced CTL. CD4+ cells are not involved in the costimulatory response in the systems examined. We conclude that CD8+ T cell activation requires two signals: an antigen-specific signal mediated by the T cell receptor, and an additional antigen nonspecific signal provided via a CD28-B7 interaction.

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