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.

Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40

10.1038/10503 ◽  
1999 ◽  
Vol 5 (7) ◽  
pp. 780-787 ◽  
Author(s):  
Eduardo M. Sotomayor ◽  
Ivan Borrello ◽  
Erev Tubb ◽  
Frédérique-Marie Rattis ◽  
Harold Bien ◽  
...  
Keyword(s):  
T Cell ◽  
Cd4 T Cell ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
T Cell Priming

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 Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin

2010 ◽  
Vol 207 (5) ◽  
pp. 999-1013 ◽  
Author(s):  
Nichole M. Danzl ◽  
Laura T. Donlin ◽  
Konstantina Alexandropoulos
Keyword(s):  
T Cell ◽  
Keratinocyte Growth Factor ◽  
Cell Receptor ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Cell ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Signaling Protein ◽  
Thymic Stroma

Medullary thymic epithelial cells (mTECs) play an important role in T cell tolerance and prevention of autoimmunity. Mice deficient in expression of the signaling protein Sin exhibit exaggerated immune responses and multitissue inflammation. Here, we show that Sin is expressed in the thymic stroma, specifically in mTECs. Sin deficiency led to thymic stroma–dependent autoimmune manifestations shown by radiation chimeras and thymic transplants in nude mice, and associated with defective mTEC-mediated elimination of thymocytes in a T cell receptor transgenic model of negative selection. Lack of Sin expression correlated with a disorganized medullary architecture and fewer functionally mature mTECs under steady–state conditions. Additionally, Sin deficiency inhibited the expansion of mTECs in response to in vivo administration of keratinocyte growth factor (KGF). These results identify Sin as a novel regulator of mTEC development and T cell tolerance, and suggest that Sin is important for homeostatic maintenance of the medullary epithelium in the adult thymus.

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.

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 Transferable Anergy: Superantigen Treatment Induces CD4+ T Cell Tolerance That Is Reversible and Requires CD4−CD8− Cells and Interferon γ

1997 ◽  
Vol 186 (1) ◽  
pp. 71-81 ◽  
Author(s):  
Linda S. Cauley ◽  
Keith A. Cauley ◽  
Fillipa Shub ◽  
Gail Huston ◽  
Susan L. Swain
Keyword(s):  
T Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Cd4 T Cell ◽  
Staphylococcal Enterotoxin A ◽  
Cd4 Cells ◽  
Cd8 Cells

Bacterial superantigens induce peripheral unresponsiveness in CD4+ T cell populations that express appropriate Vβ chains. We have used Vβ3/Vα11 T cell receptor transgenic (Tg) mice and the Vβ3-specific superantigen staphylococcal enterotoxin A (SEA) to further investigate the mechanisms that contribute to such unresponsiveness. As in other models, in vivo exposure to SEA rendered the Tg CD4+ cells unresponsive to subsequent restimulation in vitro with antigen or mitogens. However, when the SEA-treated CD4+ cells were completely purified away from all other contaminating cells, they regained the ability to proliferate and secrete cytokines. Moreover, enriched CD4−CD8− cells from the SEA-treated mice suppressed the responses of fresh control CD4+ cells in mixed cultures indicating that the apparent “anergy” was both transferable and reversible. Further analysis demonstrated that interferon γ, but not the Fas receptor, played a critical role in the suppression.

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.

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