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.

scholarly journals Expression and functional significance of an additional ligand for CTLA-4

1993 ◽  
Vol 90 (23) ◽  
pp. 11054-11058 ◽  
Author(s):  
D J Lenschow ◽  
G H Su ◽  
L A Zuckerman ◽  
N Nabavi ◽  
C L Jellis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
T Cell Proliferation ◽  
Antigen Presenting

Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.

scholarly journals Mertk Inhibition Promotes Anti-Leukemia Immunity By Reversing T Cell Suppression Via the PD-1 Axis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4019-4019
Author(s):  
Alisa Lee-Sherick ◽  
Kristen Jacobsen ◽  
Curtis J. Henry ◽  
Rebecca Parker ◽  
Xiaodong Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Suppression ◽  
Tnf Α ◽  
Equity Ownership ◽  
Cell Suppression

Abstract The efferocytic receptor MerTK is expressed on monocytes/macrophages and facilitates tolerogenic T cell suppressive clearance of apoptotic cellular debris. Given the rapid cell turn-over in leukemia, we hypothesized that ongoing efferocytosis is leukemia-permissive and inhibition of MerTK on monocytes/macrophages will reverse T cell suppression leading to enhanced anti-leukemia immunity. To test this hypothesis, we inoculated mice with syngeneic murine BCR-ABL p185 acute lymphoblastic leukemia (ALL) cells, which do not express MerTK. The effects of MerTK inhibition were evaluated in wild-type (WT) mice treated daily with MRX-2843, a MerTK small molecule inhibitor, and in mice with a MerTK knockout mutation (Mertk-/-). Median survival was prolonged in WT mice treated with MRX-2843 (40 days) compared to vehicle treatment (20 days, p<0.01). In littermate Mertk-/- mice, all but one mouse survived without evidence of leukemia 150 days after inoculation (p<0.0001). To explore the T cell suppressive effects of MerTK inhibition on CD11b+ monocytes/macrophages, we used flow cytometry to study ex vivo mixed cell cultures using Mertk-/- or WT murine splenocytes +/- ALL cells treated +/- MRX-2843. Co-culture with ALL cells for 24 (36.0%), 48 (34.9%) and 72 (36.6%) hours resulted in a significant increase in expression of co-inhibitory ligands PD-L1 and PD-L2 on CD11b+ cells compared to cultures without ALL cells (2.03%, 3.2% and 7.5%, p<0.0001), or cultures with ALL cells treated with MRX-2843 (8.3%, 15.3% and 9.5%, p<0.0001). Similarly, PD-L1/PD-L2 co-expression on CD11b+ cells from Mertk-/- mice was not significantly altered in the presence (16.0%) or absence (7.0%) of ALL. Furthermore, there was no significant change in PD-L1/PD-L2 expression when Mertk-/- co-cultures were treated with MRX-2843 (12.6%). These findings were recapitulated in vivo. There was no change in PD-L1/PD-L2 expression on CD11b+ cells from Mertk-/- mice inoculated with ALL (4.8% spleen; 0.8% marrow) compared to uninoculated Mertk-/- mice (7.2% spleen; 1.2% marrow) or uninoculated WT littermates (2.0% spleen; 0.7% bone marrow), whereas CD11b+ cells from WT mice inoculated with ALL demonstrated a significant upregulation of PD-L1/PD-L2 (24.1% spleen, p<0.0001; and 4.2% bone marrow, p<0.001), which was downregulated upon treatment with MRX-2843 (1.9% spleen, p<0.01; 1.2% bone marrow, p<0.05) In these experiments, expression of PD-1, the co-inhibitory receptor which binds PD-L1/PD-L2, on T cells was also assessed. In WT mice inoculated with ALL, expression of PD-1 on T cells from spleens (74.2% CD4+; 49.2% CD8+) and bone marrow (65.9% CD4+; 73.0% CD8+) was significantly increased compared to spleens (10.0% CD4+; 4.1% CD8+) and bone marrow (36.4% CD4+; 8.5% CD8+) from uninoculated control mice (p<0.0001). However, expression of PD-1 was not significantly different in spleens (28.3% CD4+; 7.2% CD8+) and bone marrow (66.2% CD4+; 29.2% CD8+) from Mertk-/- mice inoculated with ALL compared with spleens (20.0% CD4+; 4.7% CD8+) and bone marrow (62.2% CD4+; 12.4% CD8+) from uninoculated Mertk-/- mice. To determine whether changes in PD-1 expression were indicative of T cell activation or exhaustion, T cells treated with α-CD3 beads were added to splenocyte and ALL cell co-cultures for 24 hours and intracellular IFN-ɣ and TNF-α levels were assessed using flow cytometry. The fraction of T cells producing IFN-ɣ/TNF-α significantly increased in co-cultures treated with MRX-2843 (44.2% CD4+; 51.1% CD8+) compared to vehicle-treated co-cultures (27.4% CD4+, p<0.0001; 36.8% CD8+, p<0.0001). Similarly, IFN-ɣ/TNF-α production increased in co-cultures with Mertk-/- splenocytes and ALL cells (48.3% CD4+, p<0.0001; 51.2% CD8+, p<0.0001) compared to co-cultures with WT splenocytes and activation was not further augmented by treatment with MRX-2843 (48.9% CD4+, 51.5% CD8+). Similar results were obtained when T cells from Mertk-/-mice were used, demonstrating that the effects of T cell activation were dependent on the presence of MerTK on CD11b+ cells, but not T cells. In conclusion, inhibition of MerTK on CD11b+ monocytes/macrophages reversed T cell suppression in response to leukemia via the PD-1 axis. MerTK inhibitors are in early phase clinical trials and these data demonstrate a potential immunotherapeutic use for MerTK inhibitors in the treatment of ALL. Disclosures Wang: Meryx: Equity Ownership, Patents & Royalties. Frye:Meryx: Equity Ownership, Patents & Royalties. Earp:Meryx: Equity Ownership. DeRyckere:Meryx: Equity Ownership. Graham:Meryx: Equity Ownership.

scholarly journals Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Song Chen ◽  
Ran Ding ◽  
Yan Zhou ◽  
Xian Zhang ◽  
Rui Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interleukin 12 ◽  
Related Factors ◽  
Knock Out ◽  
Specific Immunity

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.

Regulation of Tim-3 function by binding to phosphatidylserine

2021 ◽  
Vol 478 (22) ◽  
pp. 3999-4004
Author(s):  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Transmembrane Protein ◽  
Cytotoxic T Cells ◽  
Cross Presentation ◽  
First Time

Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim-3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation.

TREM-1 modulates dendritic cell maturation and dendritic cell–mediated T cell activation induced by ox-LDL

2020 ◽  
Author(s):  
Yunkai Wang ◽  
Jie Wang ◽  
Lu Han ◽  
Yun Li Shen ◽  
Jie Yun You ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Peripheral Blood ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Blood Monocytes

Abstract Background: Triggering receptor expressed on myeloid cells (TREM)-1is identified as a major upstream proatherogenic receptor. However, the cellular processes modulated by TREM-1 in the development of atherosclerosis and plaque destabilization has not been fully elucidated. In this study, we investigated the effects of TREM-1 on dendritic cell maturation and dendritic cell–mediated T-cell activation induced by oxidized low-density lipoprotein (ox-LDL) in atherogenesis. Methods: Human peripheral blood monocytes were differentiated to dendritic cells and stimulated by ox-LDL. Naive autologous T cells were co-cultured with pretreated dendritic cells.The expressionof TREM-1 and the production of inflammatory cytokines were assessed by real-time PCR, western blot and ELISA.The expression of immune factors was determined with FACS to evaluate dendritic cell maturation and T-cell activation. Results: Stimulation with ox-LDL promoted dendritic cell maturation, TREM-1 expression and T-cell activation, and exposure of T cells to ox-LDL-treated dendritic cells induced production of interferon-γ and IL-17. Blocking TREM-1 suppressed dendritic cell maturation with low expression of CD1a, CD40, CD86 and HLA-DR, decreased production of TNF-α, IL-1β, IL-6 and MCP-1, and increased secretion of TGF-β and IL-10. In addition, stimulation of ox-LDL induced miR-155, miR-27, Let-7c and miR-185 expression, whereas inhibition of TREM-1 repressed miRNA-155. Silencing TREM-1 or miRNA-155 increased SOCS1 expression induced by ox-LDL. T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar result patterns. Conclusion: These data suggest that TREM-1 modulates maturation of dendritic cells and activation of plaque T cells induced by ox-LDL, a pivotal player in atherogenesis.

scholarly journals Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

2019 ◽  
Vol 11 (2) ◽  
pp. 108-123
Author(s):  
Dan Tong ◽  
Li Zhang ◽  
Fei Ning ◽  
Ying Xu ◽  
Xiaoyu Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Immune Memory ◽  
Term Survival

Abstract Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

scholarly journals A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1010-1017 ◽  
Author(s):  
Peta J. O'Connell ◽  
Xiangbin Wang ◽  
Matilde Leon-Ponte ◽  
Corrie Griffiths ◽  
Sandeep C. Pingle ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Activated T Cells ◽  
Immune Synapse ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
5 Ht Uptake

AbstractAdaptive immunity is triggered at the immune synapse, where peptide-major histocompatibility complexes and costimulatory molecules expressed by dendritic cells (DCs) are physically presented to T cells. Here we describe transmission of the inflammatory monoamine serotonin (5-hydroxytryptamine [5-HT]) between these cells. DCs take up 5-HT from the microenvironment and from activated T cells (that synthesize 5-HT) and this uptake is inhibited by the antidepressant, fluoxetine. Expression of 5-HT transporters (SERTs) is regulated by DC maturation, exposure to microbial stimuli, and physical interactions with T cells. Significantly, 5-HT sequestered by DCs is stored within LAMP-1+ vesicles and subsequently released via Ca2+-dependent exocytosis, which was confirmed by amperometric recordings. In turn, extracellular 5-HT can reduce T-cell levels of cAMP, a modulator of T-cell activation. Thus, through the uptake of 5-HT at sites of inflammation, and from activated T cells, DCs may shuttle 5-HT to naive T cells and thereby modulate T-cell proliferation and differentiation. These data constitute the first direct measurement of triggered exocytosis by DCs and reveal a new and rapid type of signaling that may be optimized by the intimate synaptic environment between DCs and T cells. Moreover, these results highlight an important role for 5-HT signaling in immune function and the potential consequences of commonly used drugs that target 5-HT uptake and release.

scholarly journals Triggering of TLR-3, -4, NOD2, and DC-SIGN reduces viral replication and increases T-cell activation capacity of HIV-infected human dendritic cells

2017 ◽  
Vol 47 (5) ◽  
pp. 818-829 ◽  
Author(s):  
Sylvain Cardinaud ◽  
Alejandra Urrutia ◽  
Angeline Rouers ◽  
Pierre-Grégoire Coulon ◽  
Jérome Kervevan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Viral Replication ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Dendritic Cells ◽  
Activation Capacity

DOCK8-Deficient Mice Reveal a Crucial Role for Dendritic Cell Activity in the Initiation of the Allogeneic Response to Transfused Red Blood Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 658-658
Author(s):  
Stephanie C. Eisenbarth ◽  
Jeanne E. Hendrickson ◽  
Samuele Calabro ◽  
Antonia Gallman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Innate Immune ◽  
Allogeneic Response ◽  
Deficient Mice

Abstract The generation of antibodies against transfused red blood cells (RBCs) can pose a serious health risk, especially in chronically transfused patients requiring life-long transfusion support; yet our understanding of what immune signals or cells dictate when someone will become alloimmunized is lacking. The relative role of dendritic cells, B cells and macrophages in the induction of RBC alloimmunization remain unclear. Given the now well established role of innate immune signals in regulating adaptive immunity, understanding if and how innate immunity is triggered during transfusion may allow development of therapies to prevent alloimmunization in chronically transfused subjects such as those with myelodysplasia or hemoglobinopathies. We have established a murine model system in which we can evaluate both the role of particular innate immune stimuli as well as particular cells of the immune system in regulating the allogeneic response to transfused RBCs. A particularly useful transgenic "HOD mouse" has been engineered, which encodes a triple fusion protein and provides a unique tool to directly assess both RBC-specific T and B cell responses. This RBC-specific antigen contains the model protein antigen hen egg lysozyme (HEL) fused to chicken ovalbumin (OVA) fused to the human Duffyb blood group antigen (HEL-OVA-Duffy) as an integral membrane protein under control of the beta globin promoter. Transfusion of genetically targeted mice lacking various innate immune cells or receptors allows us to screen for important immune pathways regulating the response to allogeneic RBCs. Using these models, we recently discovered that mice lacking the GEF (guanine nucleotide exchange factor) DOCK8 fail to develop alloimmunity to transfused RBCs. Dendritic cells in these knockout mice fail to migrate to T cells due to lack of coordinated actin rearrangement governed by this GEF. Both B cell and T cell activation in the spleen to the transgenic transfused RBCs is abrogated. Inclusion of OVA in the alloantigen of the HOD mice allows us to readily study naïve CD4+ T cell activation following transfusion by using the OTII T cell receptor (TCR) transgenic mice in which essentially all T cells express one antigen receptor specific for a peptide of OVA. By tracking rounds of cell division we found that adoptively transferred OTII undergo more than 5-8 rounds of division in the spleen three days following transfusion of HOD RBCs in WT recipients. In contrast, no OTII proliferation was observed in DOCK8-deficient mice following OTII adoptive transfer and HOD RBC transfusion, suggesting that T cells are failing to receive activation signals by splenic antigen presenting cells. Our preliminary data now suggest that DOCK8-deficient dendritic cells are able to process and present RBC-derived antigens, but do not migrate to T cell zones in the spleen to prime naïve RBC-specific T cells. The need for dendritic cell migration within the spleen in the induction of alloimmunity to transfused RBCs has not been addressed; these mice allow us for the first time to answer these fundamental immunologic questions during transfusion. Future work will aim to determine how dendritic cell movement within the spleen is regulated during transfusion and the specific role of splenic dendritic cell subsets in CD4+ T cell priming to allogeneic RBCs. Disclosures No relevant conflicts of interest to declare.

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