scholarly journals MerTK is required for apoptotic cell–induced T cell tolerance

2008 ◽  
Vol 205 (1) ◽  
pp. 219-232 ◽  
Author(s):  
Mark A. Wallet ◽  
Pradip Sen ◽  
Rafael R. Flores ◽  
Yaming Wang ◽  
Zuoan Yi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Autoimmune Diabetes ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Costimulatory Molecule ◽  
Nod Mice ◽  
Β Cell

Self-antigens expressed by apoptotic cells (ACs) may become targets for autoimmunity. Tolerance to these antigens is partly established by an ill-defined capacity of ACs to inhibit antigen-presenting cells such as dendritic cells (DCs). We present evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation. Pretreatment of DCs prepared from nonobese diabetic (NOD) mice with AC blocked secretion of proinflammatory cytokines, up-regulation of costimulatory molecule expression, and T cell activation. The effect of ACs on DCs was dependent on Gas6, which is a MerTK ligand. NOD DCs lacking MerTK expression (NOD.MerTKKD/KD) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTKKD/KD versus NOD mice expressing the transgenic BDC T cell receptor. In addition, β cell–specific CD4+ T cells adoptively transferred into NOD.MerTKKD/KD mice in which β cell apoptosis was induced with streptozotocin exhibited increased expansion and differentiation into type 1 T cell effectors. In both models, the lack of MerTK expression was associated with an increased frequency of activated pancreatic CD11c+CD8α+ DCs, which exhibited an enhanced T cell stimulatory capacity. These findings demonstrate that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.

scholarly journals The Role of Macrophages in T Cell–mediated Autoimmune Diabetes in Nonobese Diabetic Mice

1999 ◽  
Vol 189 (2) ◽  
pp. 347-358 ◽  
Author(s):  
Hee-Sook Jun ◽  
Chang-Soon Yoon ◽  
Lori Zbytnuik ◽  
Nico van Rooijen ◽  
Ji-Won Yoon
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Autoimmune Diabetes ◽  
Cytotoxic T Cells ◽  
Nod Mice ◽  
Β Cell ◽  
Prevention Of Diabetes

We have shown previously that the inactivation of macrophages in nonobese diabetic (NOD) mice results in the prevention of diabetes; however, the mechanisms involved remain unknown. In this study, we found that T cells in a macrophage-depleted environment lost their ability to differentiate into β cell–cytotoxic T cells, resulting in the prevention of autoimmune diabetes, but these T cells regained their β cell–cytotoxic potential when returned to a macrophage-containing environment. To learn why T cells in a macrophage-depleted environment lose their ability to kill β cells, we examined the islet antigen–specific immune response and T cell activation in macrophage-depleted NOD mice. There was a shift in the immune balance, a decrease in the T helper cell type 1 (Th1) immune response, and an increase in the Th2 immune response, due to the reduced expression of the macrophage-derived cytokine IL-12. As well, there was a deficit in T cell activation, evidenced by significant decreases in the expression of Fas ligand and perforin. The administration of IL-12 substantially reversed the prevention of diabetes in NOD mice conferred by macrophage depletion. We conclude that macrophages play an essential role in the development and activation of β cell–cytotoxic T cells that cause β cell destruction, resulting in autoimmune diabetes in NOD mice.

scholarly journals Impairment of Antigen-Presenting Cell Function in Mice Lacking Expression of Ox40 Ligand

2000 ◽  
Vol 191 (2) ◽  
pp. 365-374 ◽  
Author(s):  
Kazuko Murata ◽  
Naoto Ishii ◽  
Hiroshi Takano ◽  
Shigeto Miura ◽  
Lishomwa C. Ndhlovu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Critical Role ◽  
Costimulatory Molecule ◽  
Activated T Cells ◽  
Antigen Presenting

OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L, is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L monoclonal antibody, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-immunoglobulin (Ig)M stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice engendered apparent suppression of the recall reaction of T cells primed with both protein antigens and alloantigens and a significant reduction in keyhole limpet hemocyanin–specific IgG production. The impaired T cell priming was also accompanied by a concomitant reduction of both T helper type 1 (Th1) and Th2 cytokines. Furthermore, antigen-presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo.

scholarly journals Role of Ly-6 in lymphocyte activation. II. Induction of T cell activation by monoclonal anti-Ly-6 antibodies.

1986 ◽  
Vol 164 (3) ◽  
pp. 709-722 ◽  
Author(s):  
T R Malek ◽  
G Ortega ◽  
C Chan ◽  
R A Kroczek ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Proliferative Response ◽  
Cell Activation ◽  
Critical Role ◽  
Lymphocyte Activation ◽  
Accessory Cells ◽  
Peripheral T Cells ◽  
Activation Cascade

The Ly-6 locus controls the expression and/or encodes for alloantigenic specificities found primarily on subpopulations of murine T and B lymphocytes. We have recently identified and characterized a new rat mAb, D7, that recognizes a nonpolymorphic Ly-6 specificity. After crosslinking by anti-Ig reagents or by Fc receptor-bearing accessory cells, mAb D7 could induce IL-2 production from T cell hybridomas, and in the presence of PMA could trigger a vigorous proliferative response in resting peripheral T cells. The addition of mAb D7 to cultures of antigen- and alloantigen-, but not mitogen-stimulated T cells resulted in a marked augmentation of the proliferative response. A number of other well-characterized mAbs to Ly-6 locus products could also stimulate a T cell proliferative response after crosslinking by anti-Ig and in the presence of PMA. These results strongly suggest that Ly-6 molecules may play a critical role in the T cell activation cascade, either as receptors for an unidentified soluble or cell-associated ligand or as transducing molecules that modulate signals initiated by antigen stimulation of the T3-Ti complex.

scholarly journals Both Maturation and Survival of Human Dendritic Cells are Impaired in the Presence of Anergic/Suppressor T Cells

2003 ◽  
Vol 10 (1) ◽  
pp. 61-65 ◽  
Author(s):  
L. Frasca ◽  
C. Scottà ◽  
G. Lombardi ◽  
E. Piccolella
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
T Cell Suppression ◽  
Cell Suppression ◽  
Anergic T Cells ◽  
Human Dendritic Cells

T cell suppression is a well established phenomenon, but the mechanisms involved are still a matter of debate. Mouse anergic T cells were shown to suppress responder T cell activation by inhibiting the antigen presenting function of DC. In the present work we studied the effects of co-culturing human anergic CD4+T cells with autologous dendritic cells (DC) at different stages of maturation. Either DC maturation or survival, depending on whether immature or mature DC where used as APC, was impaired in the presence of anergic cells. Indeed, MHC and costimulatory molecule up-regulation was inhibited in immature DC, whereas apoptotic phenomena were favored in mature DC and consequently in responder T cells. Defective ligation of CD40 by CD40L (CD154) was responsible for CD95-mediated and spontaneous apoptosis of DC as well as for a failure of their maturation process. These findings indicate that lack of activation of CD40 on DC by CD40L-defective anergic cells might be the primary event involved in T cell suppression and support the role of CD40 signaling in regulating both activation and survival of DC.

Immunotherapy using activated T cells with chemotherapy for metastatic colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 767-767
Author(s):  
Yoichiro Yoshida ◽  
Naoya Aisu ◽  
Hideki Nagano ◽  
Akira Komono ◽  
Daibo Kojima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
T Cell Activation ◽  
Adoptive Immunotherapy ◽  
Cell Activation ◽  
Critical Role ◽  
Activated T Cells ◽  
Novel Technologies

767 Background: The programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. T cell activation induces effective antitumor immune response in cancer patients. Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large number of T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for metastatic colorectal cancer (mCRC). Methods: Seventeen patients with mCRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy. Results: Median age of the 17 patients (6 men, 11 women) was 64 years (range:38–80). The T cell number was more than 5.0×109 for each infusion. Median progression-free survival was 15.2 months. Response rate was 80% (complete response (CR) = 23.5%, partial response (PR) = 47.1%, stable disease (SD) = 29.4% and progressive disease (PD) = 0%). Most adverse events were mild to moderate in intensity and immunotherapy-associated toxicity was minimal. Conclusions: Combination of adoptive αβ T cell immunotherapy with chemotherapy for mCRC is safe and effective.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

scholarly journals Initiation of Autoimmune Diabetes by Developmentally Regulated Presentation of Islet Cell Antigens in the Pancreatic Lymph Nodes

1999 ◽  
Vol 189 (2) ◽  
pp. 331-339 ◽  
Author(s):  
Petter Höglund ◽  
Justine Mintern ◽  
Caroline Waltzinger ◽  
William Heath ◽  
Christophe Benoist ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Beta Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mimicry ◽  
Autoimmune Diabetes ◽  
Activated T Cells ◽  
Pancreatic Lymph Nodes

Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For example, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first “checkpoint” in diabetes progression.

scholarly journals S1P/S1PR1 Signalis Required for Optimal T-Cell Pathogenicity to Induce Gvhd By RegulatingDrp1/mTOR Axis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 643-643
Author(s):  
Linlu Tian ◽  
Yongxia Wu ◽  
Hee-Jin Choi ◽  
Xiaohui Sui ◽  
Mohammed Hanief Sofi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Xenograft Model ◽  
High Morbidity ◽  
Donor T Cells

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative option for the treatment of hematological malignancies, which is primarily mediated by donor immune cells. Acute graft-versus-host disease (aGVHD) mainly induced by transplanted donor T cells is a major and life-threating complication leading to severe "cytokines storm" and multiple organ damage, which contributes to high morbidity and mortality and thus limits the success of allo-HCT. Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is synthesized from sphingosine by sphingosine kinase 1 (Sphk1) or Sphk2 and degraded by S1P lyase. S1P signal plays an important role in regulating biological functions and homeostasis of T lymphocytes, and thus has been considered as a therapeutic candidate against autoimmune disease. In current study, we demonstrated that Sphk1 but not Sphk2 is required for antigen-presenting cells (APC) to activate allogeneic T cells. Using murine allo-HCT models, we found that secretory S1P produced by Sphk1 in the recipients was required for the development of full-blown GVHD (Fig. 1 A-B). Consistently, S1PR1, a primary receptor for S1P, plays a critical role in the pathogenicity of donor T cells to induce GVHD (Fig. 1C). Using pharmacologic inhibitors, we demonstrated that specific inhibition of Sphk1 (PF543) or S1PR1 (W146) substantially attenuated GVHD while preserving graft-vs.-leukemia (GVL) effect (Fig. 1D). Mechanistically, S1P/S1PR1 signal facilitated T-cell activation and differentiation towards Th1/Th17 but away from Tregs (Fig. 1E) and also promoted T-cell migratory potential into GVHD target organs (Fig. 1F). S1P/S1PR1 signaling increased mitochondrial fission of pathogenic CD4 + T cells through PRKAA1 dependent Drp1 and phosphorylated S6 (pS6) activation (Fig. 1 G-H). Whereas CD8 + T cells were much less sensitive to S1P-S1PR1-PRKAA1-pS6/Drp1 axis, which likely contributed to the GVL maintenance when S1P/S1PR1 signaling is absent or inhibited (Fig. 1 D, G). Furthermore, clinical data demonstrated that patients with acute GVHD exhibited a comparable level of sphingosine but a significantly higher level of S1P, as compared to the patients without GVHD, suggesting a positive role of S1P in GVHD development in clinic (Fig. 1I). Finally, we validated the efficacy of inhibiting Sphk1/S1PR1 in GVHD prevention induced by human T cells in a xenograft model (Fig. 1J). Taken together, our results provide a rationale and novel mechanism of targeting Sphk1/S1PR1 in the prevention of GVHD and leukemia relapse after allo-HCT. This novel strategy may be translated in the clinic to benefit patients with hematologic malignancies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

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