scholarly journals Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

2016 ◽  
Vol 113 (38) ◽  
pp. 10649-10654 ◽  
Author(s):  
Verena Schuette ◽  
Maria Embgenbroich ◽  
Thomas Ulas ◽  
Meike Welz ◽  
Jonas Schulte-Schrepping ◽  
...  
Keyword(s):  
T Cell ◽  
Cytotoxic T Lymphocyte ◽  
Cell Activity ◽  
Direct Interaction ◽  
B Cell Lymphoma ◽  
Mannose Receptor ◽  
T Cell Tolerance ◽  
Cell Tolerance

The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8+ T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte–associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.

scholarly journals Loss of Zbtb32 in NOD mice does not significantly alter T cell responses.

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 318
Author(s):  
William D. Coley ◽  
Yongge Zhao ◽  
Charles J. Benck ◽  
Yi Liu ◽  
Chie Hotta-Iwamura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nod Mice ◽  
Diabetes Incidence ◽  
T Cell Tolerance ◽  
Cell Tolerance

Background: We previously identified the transcriptional regulator Zbtb32 as a factor that can promote T cell tolerance in the Non-Obese Diabetic (NOD) mouse, a model of Type 1 diabetes. Antigen targeted to DCIR2+ dendritic cells (DCs) in vivo inhibited both diabetes and effector T cell expansion in NOD mice. Furthermore, Zbtb32 was preferentially induced in autoreactive CD4 T cells stimulated by these tolerogenic DCIR2+ DCs, and overexpression of Zbtb32 in islet-specific T cells inhibited the diabetes development by limiting T cell proliferation and cytokine production. Methods: To further understand the role of Zbtb32 in T cell tolerance induction, we have now used CRISPR to target the Zbtb32 gene for deletion directly in NOD mice and characterized the mutant mice. We hypothesized that the systemic loss of Zbtb32 in NOD mice would lead to increased T cell activation and increased diabetes pathogenesis. Results: Although NOD.Zbtb32-/- male NOD mice showed a trend towards increased diabetes incidence compared to littermate controls, the difference was not significant. Furthermore, no significant alteration in lymphocyte number or function was observed. Importantly, in vitro stimulation of lymphocytes from NOD.Zbtb32-/- mice did not produce the expected hypersensitive phenotype observed in other genetic strains, potentially due to compensation by homologous genes. Conclusions: The loss of Zbtb32 in the NOD background does not result in the expected T cell activation phenotype.

scholarly journals In situ induction of dendritic cell–based T cell tolerance in humanized mice and nonhuman primates

2011 ◽  
Vol 208 (12) ◽  
pp. 2477-2488 ◽  
Author(s):  
Kyeong Cheon Jung ◽  
Chung-Gyu Park ◽  
Yoon Kyung Jeon ◽  
Hyo Jin Park ◽  
Young Larn Ban ◽  
...  
Keyword(s):  
T Cell ◽  
Humanized Mice ◽  
Intercellular Adhesion Molecule ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Intercellular Adhesion Molecule 1 ◽  
Porcine Islet

Induction of antigen-specific T cell tolerance would aid treatment of diverse immunological disorders and help prevent allograft rejection and graft versus host disease. In this study, we establish a method of inducing antigen-specific T cell tolerance in situ in diabetic humanized mice and Rhesus monkeys receiving porcine islet xenografts. Antigen-specific T cell tolerance is induced by administration of an antibody ligating a particular epitope on ICAM-1 (intercellular adhesion molecule 1). Antibody-mediated ligation of ICAM-1 on dendritic cells (DCs) led to the arrest of DCs in a semimature stage in vitro and in vivo. Ablation of DCs from mice completely abrogated anti–ICAM-1–induced antigen-specific T cell tolerance. T cell responses to unrelated antigens remained unaffected. In situ induction of DC-mediated T cell tolerance using this method may represent a potent therapeutic tool for preventing graft rejection.

Analysis of the Fate and Function of Antigen-Specific CD8 T Cells during B Cell Lymphoma Progression.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 80-80 ◽  
Author(s):  
Jason Brayer ◽  
Fengdong Cheng ◽  
Pedro Horna ◽  
Ildefonso Suarez ◽  
Hongwei Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
B Cell Lymphoma ◽  
Cd8 T Cell ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Stat3 Signaling ◽  
And Function

Abstract There is now overwhelming evidence that tumor-induced antigen (Ag)-specific T cell tolerance represents a critical problem in tumor immunology. Early studies of CD8 T cell tolerance equated peripheral tolerance with either ignorance or clonal deletion, although more recent evidence has suggested that this may be only partly accurate. While murine modeling outwardly supports the contention that high-affinity tumor-specific CD8 T cell responses are centrally deleted, cognate CD8 T cells displaying an Ag-experienced phenotype can nonetheless be detected in regional draining lymph nodes (dLN) or in non-lymphoid sites where the Ag is present. However, these CD8 T cells are typically deficient in one or more effector functions, including cytokine production, cytotoxicity, or proliferative capacity. To better define the state of Ag-specific CD8 T cell responsiveness in the face of progressive tumor, we adoptively transferred hemagglutinin (HA) Ag-specific Clone 4 (CLN4) CD8 T cells into animals bearing a genetically modified B cell lymphoma expressing HA as a model tumor antigen (A20HA). Analysis of the fate and function of these transferred antigen-specific CD8 T cells revealed that they encountered antigen in vivo, were capable of mounting an initial response to A20HA but this response was not sustained. Indeed, while a prominent CTL activation was observed in the spleen and draining lymph nodes of tumor bearing mice within 14 days of T cell transfer, responses (HA-specific proliferation, IFN-γ production and cytotoxicity) began to wane by day 21 after T cell transfer, and in particular their ability to produce IFN-γ. A similar pattern of transient activation followed by loss of CD8 T cell function has been also observed in an in vivo model of high-dose peptide induced antigen-specific CD8 T cell tolerance. Given our recent demonstration that the disruption of Stat3 signaling in APCs overcomes CD4 T cell tolerance we determined next whether Stat3 deficient APCs may be inherently better at cross-presenting tumor-Ags and elicit therefore a more productive and sustained CD8 T cell response. In an in vitro system in which tumor cells expressing a model tumor antigen (EL4mOVA) were cultured with APCs genetically devoid of Stat3 signaling and anti-OVA CD8 T-cells (OT-I), we found that these T cells displayed an enhanced function relative to antigen-specific CD8 T-cells that encountered antigen on APCs with an intact Stat3 signaling. Currently, we are investigating whether CD8 T-cell tolerance to tumor antigens occurred -or not- in tumor bearing mice with a genetic disruption of Stat3 signaling in APCs. Furthermore, given the emerging role of other members of the STAT family in regulation of APC function, we are exploring whether targeted disruption of Stat1, 4 and 6 can alter the ability of the CD8 T-cell to sustain a protective response or, more importantly to recover function once tolerance is induced.

scholarly journals Loss of Zbtb32 in NOD mice does not significantly alter T cell responses.

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 318
Author(s):  
William D. Coley ◽  
Yongge Zhao ◽  
Charles J. Benck ◽  
Yi Liu ◽  
Chie Hotta-Iwamura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nod Mice ◽  
Diabetes Incidence ◽  
T Cell Tolerance ◽  
Cell Tolerance

Background:We previously identified the transcriptional regulator Zbtb32 as a factor that can promote T cell tolerance in the Non-Obese Diabetic (NOD) mouse, a model of Type 1 diabetes. Antigen targeted to DCIR2+dendritic cells (DCs)in vivoinhibited both diabetes and effector T cell expansion in NOD mice. Furthermore, Zbtb32 was preferentially induced in autoreactive CD4 T cells stimulated by these tolerogenic DCIR2+DCs, and overexpression of Zbtb32 in islet-specific T cells inhibited the diabetes development by limiting T cell proliferation and cytokine production.Methods:To further understand the role of Zbtb32 in T cell tolerance induction, we have now used CRISPR to target the Zbtb32 gene for deletion directly in NOD mice and characterized the mutant mice. We hypothesized that the systemic loss of Zbtb32 in NOD mice would lead to increased T cell activation and increased diabetes pathogenesis.Results:Although NOD.Zbtb32-/-male NOD mice showed a trend towards increased diabetes incidence compared to littermate controls, the difference was not significant. Furthermore, no significant alteration in lymphocyte number or function was observed. Importantly,in vitrostimulation of lymphocytes from NOD.Zbtb32-/-mice did not produce the expected hypersensitive phenotype observed in other genetic strains, potentially due to compensation by homologous genes.Conclusions:The loss of Zbtb32 in the NOD background does not result in the expected T cell activation phenotype.

scholarly journals New emerging targets in cancer immunotherapy: the role of GITR

ESMO Open ◽  
2020 ◽  
Vol 4 (Suppl 3) ◽  
pp. e000738
Author(s):  
Giulia Buzzatti ◽  
Chiara Dellepiane ◽  
Lucia Del Mastro
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Antitumour Activity ◽  
Cell Activity ◽  
Phase I Clinical Trials ◽  
Effector T Cell ◽  
Number Of Patients

In the last decade, immunotherapies have revolutionised anticancer treatment. However, there is still a number of patients that do not respond or acquire resistance to these treatments. Despite several efforts to combine immunotherapy with other strategies like chemotherapy, or other immunotherapy, there is an ‘urgent’ need to better understand the immune landscape of the tumour microenvironment. New promising approaches, in addition to blocking co-inhibitory pathways, such those cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 mediated, consist of activating co-stimulatory pathways to enhance antitumour immune responses. Among several new targets, glucocorticoid-induced TNFR-related gene (GITR) activation can promote effector T-cell function and inhibit regulatory T-cell (Treg) function. Preclinical data on GITR-agonist monoclonal antibodies (mAbs) demonstrated antitumour activity in vitro and in vivo enhancing CD8+ and CD4+ effector T-cell activity and depleting tumour-infiltrating Tregs. Phase I clinical trials reported a manageable safety profile of GITR mAbs. However, monotherapy seems not to be effective, whereas responses have been reported in combination therapy, in particular adding PD-1 blockade. Several clinical studies are ongoing and results are awaited to further develop GITR-stimulating treatments.

Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 969-977 ◽  
Author(s):  
Eric Dobrzynski ◽  
Federico Mingozzi ◽  
Yi-Lin Liu ◽  
Elisabeth Bendo ◽  
Ou Cao ◽  
...  
Keyword(s):  
T Cell ◽  
Gene Transfer ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Viral Gene ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Viral Gene Transfer

AbstractImmune responses to the therapeutic gene product are a potentially serious complication in treatment of genetic disease by gene therapy. Induction and maintenance of immunologic hypo-responsiveness to the therapeutic antigen is therefore critical to the success of gene-based treatment of inherited protein deficiency. Here, we demonstrate induction of antigen-specific CD4+ T-cell tolerance to a secreted transgene product (ovalbumin, ova) in ova-specific T-cell receptor (TCR) transgenic mice by hepatic adeno-associated virus (AAV)–mediated gene transfer. Transduced mice maintained stable circulating ova levels without evidence of an immune response. Lymph node cells and splenocytes were hypo-responsive to ova as early as day 10 after gene transfer. Numbers of TCR+CD4+ cells were reduced in secondary lymphoid organs and in the thymus by 1 to 2 months after vector administration. The remaining TCR+CD4+ cell population was anergic to ova antigen in vitro and enriched for CD25+ cells. These data provide direct evidence that transgene expression following in vivo viral gene transfer can induce CD4+ T-cell tolerance to the transgene product, involving anergy and deletion mechanisms.

scholarly journals Peripheral but Not Central Tolerance Regulates RBC Autoreactive CD4+ T Cells in a Novel Mouse

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3441-3441
Author(s):  
Sut Ling Wong ◽  
Amanda L Richards ◽  
James C. Zimring ◽  
Krystalyn E. Hudson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Tolerance Mechanisms ◽  
Ki 67 ◽  
Central Tolerance

Abstract Background: Elucidating the mechanisms of T cell tolerance towards autoantigens can be critical for therapeutic efforts to re-establish tolerance in autoimmune diseases or break tolerance in tumor immunotherapy. Tolerance mechanisms have been well described towards tissue-restricted antigens and include deletion, anergy, or regulatory cells; however, T cell tolerance mechanisms against RBC-restricted antigens are poorly understood. Herein, we utilized the HOD mouse to investigate T cell tolerance mechanisms to RBC-specific antigens. The HOD mouse expresses a triple fusion protein consisting of hen egg lysosyme (H EL), ovalbumin (O VA), and human blood group molecule, D uffy (HOD) driven by a RBC-specific promoter. A TCR transgenic mouse that recognizes an OVA peptide presented by MHI II (OT-II mouse) was crossed with the HOD mouse to allow analysis of T cells autoreactive to an RBC specific antigen. Methods: To evaluate central tolerance, OVA specific T cells were analyzed from thymii from 6-8 weeks old OT-II+ HOD+ mice (OT-II+ HOD- littermates were used as controls for T cells in absence of autoantigen). Splenic CD4+ T cells from both OT-II+ HOD+ and control OT-II+ HOD- mice were CFSE-labeled and analyzed 1) in vitro by co-culturing with splenocytes pulsed with whole soluble OVA or 2) in vivo by adoptively transferring into B6.Thy1.1 recipients, followed by transfusion of HOD RBC. Proliferative responses of cells were measured by CFSE dilution analyzed with flow cytometry. Results: There is no detectable autoantibody production against the HOD antigen in OT-II+ HOD+ mice. In the thymus, similar frequencies and total nbers of OVA-specific CD4+ single positive (SP) T cells were observed between OT-II+ HOD+ and OT-II+ HOD- mice. This was not because OT-II+ HOD+ mice were incapable of deleting autoreactive T cells, since OT-II+ HOD+ mice i.v injected with soluble whole OVA, known to induce deletion, had a significant decrease in the CD4+ SP T cells. Phenotypic analysis of mature CD4+ T cells in the spleen revealed fewer OVA-specific CD4+ T cells in OT-II+ HOD+ compared to OT-II+ HOD- mice (p=0.009). The CD4+ T cells present in OT-II+ HOD+ expressed higher levels of markers associated with T cell activation and proliferation such as CD69, CD44, Ki-67 and also decreased levels of L-selection. Moreover, these cells expressed elevated levels of markers associated with T cell anergy and tolerance, including PD-1, CD5 and LAG-3. Finally, OT-II+ HOD+ mice exhibited increased numbers of CD25+ Foxp3+ Tregs (p=0.007). In 2 of 2 experiments (3 mice/group), adoptively transferred CD4+ cells from OT-II+ HOD+ did not proliferate in response to HOD RBCs while OT-II+ HOD- exhibited robust proliferation. In contrast to the in vivo results, CD4+ cells from OT-II+ HOD+ proliferated when co-cultured with splenocytes + whole soluble OVA in vitro. Conclusions : We describe a model in which regulation of CD4+ T cells autoreactive for self-RBC antigen can be studied. Although a significant number of RBC autoreactive T cells are present, and appear to have seen antigen, been activated (i.e. increased CD69 and CD44), and proliferated (increased Ki-67); these cells are nevertheless anergic as indicated by adoptive transfer studies. The ability to proliferate in vitro but not in vivo in response to HOD RBC suggests that removal from the normal in vivo environment removes inhibitory factors, consistent with peripheral tolerance mechanisms in vivo. Indeed, increased Tregs were observed in autoreactive mice compared to control mice. In contrast, thymic deletion seems to play little or no role in this case. Together, these findings identify peripheral and not central tolerance as major control mechanisms of RBC autoreactive CD4+ T cells. Mechanisms may include alterations in expression of PD-1, CD5, and LAG-3 by autoreactive cells. Disclosures Zimring: BloodworksNW: Patents & Royalties: Patent Application filed on technology in this abstract - no royalties; Immucor Inc.: Research Funding.

scholarly journals Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function

2001 ◽  
Vol 193 (11) ◽  
pp. 1295-1302 ◽  
Author(s):  
Megan K. Levings ◽  
Romina Sangregorio ◽  
Maria-Grazia Roncarolo
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
T Regulatory Cells ◽  
Transforming Growth Factor ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Major Advance ◽  
Loss Of Function

Active suppression by T regulatory (Tr) cells plays an important role in the downregulation of T cell responses to foreign and self-antigens. Mouse CD4+ Tr cells that express CD25 possess remarkable suppressive activity in vitro and in autoimmune disease models in vivo. Thus far, the existence of a similar subset of CD25+CD4+ Tr cells in humans has not been reported. Here we show that human CD25+CD4+ Tr cells isolated from peripheral blood failed to proliferate and displayed reduced expression of CD40 ligand (CD40L), in response to T cell receptor–mediated polyclonal activation, but strongly upregulated cytotoxic T lymphocyte–associated antigen (CTLA)-4. Human CD25+CD4+ Tr cells also did not proliferate in response to allogeneic antigen-presenting cells, but they produced interleukin (IL)-10, transforming growth factor (TGF)-β, low levels of interferon (IFN)-γ, and no IL-4 or IL-2. Importantly, CD25+CD4+ Tr cells strongly inhibited the proliferative responses of both naive and memory CD4+ T cells to alloantigens, but neither IL-10, TGF-β, nor CTLA-4 seemed to be directly required for their suppressive effects. CD25+CD4+ Tr cells could be expanded in vitro in the presence of IL-2 and allogeneic feeder cells and maintained their suppressive capacities. These findings that CD25+CD4+ Tr cells with immunosuppressive effects can be isolated from peripheral blood and expanded in vitro without loss of function represent a major advance towards the therapeutic use of these cells in T cell–mediated diseases.

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

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