Decreased Expression of Indoleamine 2,3-Dioxygenase 1 in Dendritic Cells From Patients with Immune Thrombocytopenia Induces Impaired Regulatory T-Cell Development

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 696-696
Author(s):  
Lucia Catani ◽  
Daria Sollazzo ◽  
Sara Trabanelli ◽  
Cecilia Evangelisti ◽  
Antonio Curti ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Copy Number ◽  
Healthy Subjects ◽  
Immune Thrombocytopenia ◽  
Healthy Controls ◽  
Ido1 Expression ◽  
Expression Activity ◽  
The Mean

Abstract Abstract 696 Regulatory T cells (Tregs) are a subset of T cells involved in the maintenance of peripheral self-tolerance. Specifically, Tregs modulate the maturation and/or function of dendritic cells (DCs). In turn, along with their immunogenic role, DCs are also critical in maintaining tolerance to self-antigens by inducing Tregs via the expression of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1-expressing DCs may play a role in preventing the initiation of autoimmune disorders. Immune Thrombocytopenia (ITP) is an autoimmune disorder in which platelet surface proteins become antigenic and stimulate the immune system. However, in ITP, the interaction between DCs and Tregs has never been investigated, although decreased numbers of Tregs as well as altered DCs have been described. Therefore, in the present study, we investigated whether, in ITP: 1) IDO1 expression/activity is decreased in monocyte-derived DCs (Mo-DCs); 2) the mechanism of Tregs generation is impaired; 3) Mo-DCs maturation is abnormally modulated by Tregs. We studied 54 patients with active ITP. Nineteen patients were newly diagnosed and 35 patients had persistent (25 cases) or chronic (10 cases) ITP. At the time of samples collection, all patients with persistent or chronic ITP were out of any treatment for at least two months and none of the patients received previous treatment with rituximab or were splenectomized. We demonstrated that in mature Mo-DCs from ITP patients the absolute number of IDO1 transcripts was significantly reduced as compared with healthy donors (973.000±771.000 vs 2.409.000±1.592.000 (IDO1 copy number/ABL1 copy number)*10.000; p<0.04). Accordingly, when we evaluated kynurenine levels as an index of IDO1 enzyme activity, we found that kynurenine concentration in the supernatants from equal numbers of mature Mo-DCs was significantly lower in ITP patients (40.7±12.5 μM) as compared to healthy subjects (66.5±9.4 μM) (p<0.05). We therefore assessed whether in ITP Mo-DCs, which have IDO1 reduced expression and activity, are less efficient in generating Tregs in vitro. We found that after co-cultures of Mo-DCs from healthy subjects or ITP patients with autologous CD4+CD25− T cells, the mean percentage of FoxP3+ cells (gated on CD4+CD25high T cells) was significantly reduced in ITP patients (54.4±4.5%) in comparison with that of healthy individuals (88.3±5.8%; p<0.01). When we evaluated whether these in vitro generated Tregs possess suppressive activity, we demonstrated that the inhibition of the proliferative response of CD4+CD25− cells in coculture with autologous in vitro generated CD4+CD25+ T cells (100:1 ratio) was significantly lower in ITP patients (25±4%) as compared with healthy controls (47±6%; p<0.05). To evaluate whether Tregs induce functional differences in Mo-DCs, we first assessed the production of cytokines in the supernatants of normal immature Mo-DCs co-cultured with highly purified circulating CD4+CD25+ or CD4+CD25− T cells from ITP patients or healthy controls. We found that in ITP patients the concentration of IL-10 was significantly reduced in the supernatant of Mo-DCs plus CD4+CD25+ T cells as compared with the normal counterparts (99±26 pg/mL vs 218±19 pg/mL; p<0.01). However, since IL-10 plays a central role in immune tolerance and can be produced by either DCs or T cells, we performed the intracytoplasmic staining of IL-10 to evaluate whether its secretion was due to Mo-DCs upon co-culture and/or produced by Tregs. The mean percentage of IL-10-producing Tregs was significantly lower in ITP patients (19.3±8.0 %) in comparison with that of normal individuals (34.9±6.6 %; p<0.04).We therefore analyzed the capacity of highly purified circulating Tregs of inhibiting Mo-DCs maturation. We found that, at variance with healthy controls, highly purified CD4+CD25+ T cells from ITP patients failed to inhibit the expression of CD80 and CD86 molecules on Mo-DCs. In summary, this study demonstrates that in ITP low IDO1 expression/activity in DCs results in the reduced ability of generating Tregs. In turn, circulating Tregs with impaired IL-10 production show decreased capacity of inhibiting DCs maturation. Taken together these data suggest that in ITP the cross-talk between Tregs and DCs is hampered and plays a pathogenetic role. As a consequence, DCs are less “tolerogenic” and Tregs are defective in their regulatory function. Disclosures: No relevant conflicts of interest to declare.

Decreased Expression of Indoleamine 2,3-Dioxygenase 1 (IDO 1) in Dendritic Cells From Patients with Immune Thrombocytopenia (ITP) Correlates with Impaired Regulatory T Cells Development

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2770-2770
Author(s):  
Lucia Catani ◽  
Daria Sollazzo ◽  
Antonio Curti ◽  
Sara Trabanelli ◽  
Cecilia Evangelisti ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Healthy Subjects ◽  
Effector T Cells ◽  
Pathogenetic Role ◽  
Chronic Itp ◽  
Ido1 Expression

Abstract Abstract 2770 Recent studies suggest a bi-directional interaction between regulatory T cells (Tregs) and dendritic cells (DCs). Despite their role as inducers of immunity, DCs may also be critical in maintaining tolerance to self-antigens by inducing Tregs. Specifically, Indoleamine 2,3-dioxygenase 1 (IDO 1) expressing DCs expand Tregs. In turn, Tregs, which express CTLA4, engage its receptors B7-1(CD80)/B7-2(CD86), thus inducing the expression of IDO1 enzyme in DCs. IDO1 expression leads to tryptophan depletion and immunosuppressive kynurenine enrichment in the tissue. Both factors drive the de novo generation of Tregs from CD4+ T cells. In addition, Tregs may modulate the maturation and/or function of DCs, which are required for the activation of effector T cells. Tregs out compete with naïve T cells in aggregating around DCs. After forming aggregates, Tregs specifically downregulate the expression of CD80 and CD86 on DCs. The result of the interaction between Tregs and DCs is the impaired capacity of the antigen presenting cells to establish long lasting interactions with effector T cells. Therefore, given the crucial role of DCs and Tregs in initiating, regulating, maintaining or repressing immune responses, investigations on their interaction is of great importance for better elucidating the pathogenesis of ITP. Of note, in ITP this interaction and its pathogenetic role have never been investigated in depth. In this paper, we enumerated and functionally characterized Treg subsets, exploring whether in ITP abnormal Tregs interactions with DCs and/or effector T cells might play a pathogenetic role. Specifically, we studied whether, in ITP patients: 1) DCs maturation is differentially modulated by Tregs from ITP patients as compared with healthy donors; 2) the mechanism of Tregs generation is altered. Forty adult ITP patients, newly diagnosed (14 cases) or with persistent (20 cases) or chronic ITP (9 cases) were studied after informed consent. At the time of the study, patients with persistent or chronic ITP were out off therapy by at least two months. None of the patients were splenectomized. The median platelet count at the time of the study was 53×109/L (range 8–99). Allogeneic Mixed Leukocyte Reaction (MLR) was performed to test the suppressive activity of Tregs. To analyze the in vitro ability of highly purified CD4+CD25+ T cells to inhibit DCs maturation, normal immature CD14-derived DCs were cultured alone and with allogeneic CD4+CD25+ T cells from healthy subjects or ITP patients in the presence of Lipopolysaccaryde. CD80 and CD86 expression of CD14-derived DCs was then tested at flow cytometry. To evaluate the in vitro conversion of non Tregs into Tregs, CD4+CD25- T cells were cultured alone and with autologous mature CD14-derived DCs from ITP patients and healthy subjects. The percentages of CD4+CD25highFoxP3+ T cells were quantitated at flow cytometry. mRNA IDO1 expression of immature and mature CD14-derived DCs was then evaluated by Real-time RT-PCR. To determine IDO1 enzyme activity kynurenine levels were measured in the supernantants of mature CD14-derived DCs. We found that in ITP Tregs show lower ability to suppress T cell proliferation and to inhibit CD14-derived DCs maturation because they do not affect the expression of the costimulatory molecules CD80 and CD86. We show that the absolute number of Tregs was significantly decreased in ITP patients in comparison to healthy subjects (CD4+CD25highFoxp3+ T cells (5.5±4.3 vs 11.6±6.9 cells/microL; p below 0.01) and CD4+CD25highCD127low/negative T cells (50.9±27.3 vs 80.5±37.7 cells/microL; p below 0.02)). In addition, in ITP patients we document that the low number of circulating Tregs may be due to the reduced ability of mature CD14-derived DCs to convert non-Treg cells (CD4+CD25-) into Tregs (CD4+CD25highFoxP3+ Tregs). This is related to reduced expression and activity of the IDO1 enzyme in mature CD14-derived DCs from ITP patients, since DCs expressing IDO1 favour Treg generation. In conclusion, taken together our data demonstrate that in ITP the cross-talk between Tregs and DCs is impaired and plays a pathogenetic role. As a consequence, we found the generation of more immunogenic DCs and defective Tregs. Disclosures: No relevant conflicts of interest to declare.

Impaired Interaction Between Regulatory T Cells and Dendritic Cells in Immune Thrombocytopenia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3511-3511
Author(s):  
Lucia Catani ◽  
Daria Sollazzo ◽  
Antonio Curti ◽  
Sara Trabanelli ◽  
Francesca Palandri ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Healthy Subjects ◽  
Immune Thrombocytopenia ◽  
Suppressive Activity ◽  
Immune Disorder ◽  
Pathogenetic Role

Abstract Abstract 3511 Poster Board III-448 CD4+CD25+ regulatory T cells (Tregs) are critical in maintaining self-tolerance and preventing organ-specific autoimmune diseases. However, the role of Tregs in the pathogenesis of immune thrombocytopenia (ITP), an immune disorder in which increased platelet clearance is caused by antiplatelet autoantibodies, has not yet been clarified. The purpose of the present study was to investigate whether the interaction between dendritic cells (DCs) and regulatory T cells (Tregs) may play a pathogenetic role in ITP. Forty patients with active disease and 35 healthy subjects were enrolled into the study. We firstly characterized the number (by flow cytometry) and the suppressive activity (by modified allogeneic mixed leukocyte reaction) of Tregs in ITP. We found that the absolute number of Tregs was significantly decreased in ITP patients in comparison to healthy subjects (CD4+CD25highFoxp3+ T cells (5.5±4.3 vs 11.6±6.9 cells/microL; p below 0.01) and CD4+CD25highCD127low-negative T cells (50.9±27.3 vs 80.5±37.7 cells/microL; p below 0.02)). We documented also that in ITP suppressive activity of Tregs was defective as compared to healthy subjects. In parallel experiments we studied the in vitro conversion of CD4+CD25- T cells, either from ITP patients or healthy subjects, into CD4+CD25+Foxp3+ Tregs by co-coltures with mature autologous/allogeneic DCs. The flow cytometry analysis showed that in ITP the low number of circulating Tregs may be partly due to the reduced ability of DCs to convert non-Treg cells into Tregs. We then explored the in vitro capability of CD4+CD25+ Tregs, either from ITP patients or healthy subjects, to inhibit allogeneic DCs maturation by flow cytometry evaluation of the expression of the costimulatory molecules CD80 and CD86. We demonstrated that in ITP patients CD4+CD25+ Tregs show lower ability to inhibit DCs maturation because they do not affect the expression of CD80 and CD86 molecules. This finding may be related to the lower level of Interleukin-10 and Interleukin-6 in the cocoltures. Taken together, these findings document that the interaction between DCs and Tregs is altered in ITP and suggest that this dysfunction may play a pathogenetic role. Supported in part by BolognaAIL (Italian association against Leukemia, Bologna section) Disclosures: No relevant conflicts of interest to declare.

Platelets from Patients with Myocardial Infarction Can Activate T Cells in Vitro

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3448-3448 ◽  
Author(s):  
Elena E. Solomou ◽  
Vasilios Gizas ◽  
Theodora Babali ◽  
Angelos Perperis ◽  
Evgenia Verigou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
T Cells ◽  
T Cell ◽  
Unstable Angina ◽  
T Cell Activation ◽  
Healthy Subjects ◽  
Cell Activation ◽  
Control Group ◽  
Healthy Controls

Abstract Specific aim: Our aim was to examine whether T cells can be activated by the circulating activated platelets from patients with myocardial infarction (with ST elevation-STEMI) Methods: After written informed consent was obtained, peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood obtained from 20 patients with STEMI (18 men and 2 women) at the time of hospital admission at diagnosis, before receiving any treatment, as well as 5 days and 30 days later. We also analyzed 10 healthy subjects (8 men and 2 women), and 5 patients with unstable angina who served as the disease control group. PBMCs were analyzed by flow cytometry with the following markers and their isotypic controls: CD4, CD25, CD69, and FOXP3. We also isolated platelet rich plasma or plasma alone from the patients and the healthy subjects, and used in mixed cultures with PBMCs. Results: We first examined T cell activation by measuring CD69 expression on CD4 T cells following incubation with platelets obtained from patients with STEMI. T cells treated with platelets from patients with STEMI showed increased expression of CD69 (as an activation marker) compared with T cells treated with platelets from healthy subjects (p<0.05, Figure 1). There was no T cell activation following incubation with plasma alone from patients or healthy controls. We then examined the percentages of CD4+CD25+hi (regulatory T cells). There was no statistical difference in Tregs between patients at presentation and controls (healthy subjects and disease control group). Five days later, patients with STEMI displayed increased levels of Tregs compared with the 2 control groups; one month later, Treg numbers returned to the initial presentation levels (p<0.05, Figure 2) Conclusion: To our knowledge we describe for the first time that platelets from patients with STEMI can activate T cells in vitro. In patients with STEMI, an increase in Tregs possibly in an effort to suppress immune system activation secondary to platelet activation, appears shortly after the infarct and normalizes a month later. Figure 1. T cell activation after treatment with platelets from patients with STEMI compared with the platelets from healthy controls or plasma alone Figure 1. T cell activation after treatment with platelets from patients with STEMI compared with the platelets from healthy controls or plasma alone Figure 2. Increased T regs in patients with STEMI , 5 days after admission (STEMI EXIT) ( UA;unstable angina, STEMI 1mfup; STEMI after one month) Figure 2. Increased T regs in patients with STEMI , 5 days after admission (STEMI EXIT) ( UA;unstable angina, STEMI 1mfup; STEMI after one month) Disclosures No relevant conflicts of interest to declare.

CRYAB modulates the activation of CD4+ T cells from relapsing–remitting multiple sclerosis patients

2013 ◽  
Vol 19 (14) ◽  
pp. 1867-1877 ◽  
Author(s):  
Que Lan Quach ◽  
Luanne M Metz ◽  
Jenna C Thomas ◽  
Jonathan B Rothbard ◽  
Lawrence Steinman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Cytokine Production ◽  
Clinical Signs ◽  
Healthy Controls ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Background: Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS. Objective: We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease. Methods: CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated. Results: The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Further, there was a correlation for higher levels of miR181a microRNA, a marker upregulated in tolerant CD8+ T cells, in CD4+ T cells of MS patients that displayed suppressed cytokine production (responders). Conclusion: CRYAB may be capable of suppressing the activation of CD4+ T cells from a subset of RRMS patients who appear to have less disability but similar age and disease duration.

scholarly journals Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

1992 ◽  
Vol 176 (5) ◽  
pp. 1431-1437 ◽  
Author(s):  
M Croft ◽  
D D Duncan ◽  
S L Swain
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 Cells ◽  
Peptide Antigen ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

scholarly journals In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

2006 ◽  
Vol 74 (7) ◽  
pp. 3817-3824 ◽  
Author(s):  
Karen L. Wozniak ◽  
Jatin M. Vyas ◽  
Stuart M. Levitz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

scholarly journals P01.02 TLR-mediated suppression of the CCL22-CCR4 axis as a new target for tumor immunotherapy

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A3.2-A4
Author(s):  
J Grün ◽  
I Piseddu ◽  
C Perleberg ◽  
N Röhrle ◽  
S Endres ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
Type I ◽  
List Type ◽  
Gm Csf

BackgroundUnmethylated CpG-DNA is a potent ligand for the endosomal Toll-like-receptor-9, important for the immune activation to pathogen-associated molecules.1 CpG and other TLR-ligands show effective immunotherapeutic capacities in cancer treatment by inducing an antitumorigenic immunity.2 They are able to reduce tumor progression by reduction of intratumoral secretion of the immunoregulating chemokine CCL223 and subsequent recruitment of immunosuppressive regulatory T cells (Treg), which express CCR4 the only so far known receptor for CCL22.4 Our recent work has shown that CCL22 secretion by dendritic cells (DC) in the lymph node, mediates tolerance by inducing DC-Treg contacts.5 Indeed, in the absence of CCL22, immune responses to vaccination were stronger and resulted in tumor rejection.6 Therefore, we are aiming to investigate the effects of TLR-ligands on systemic CCL22 levels, elucidating all involved mechanisms to identify new targets for cancer immunotherapy.Materials and MethodsT, B and CD11c+ DCs of wildtype (wt) and RAG1-/- mice were isolated from splenocytes by magnetic-activated cell sorting for in vitro assays. Different co-cultures were incubated with CpG and GM-CSF, known as an CCL22 inducer.5 For in vivo experiments, wt mice were treated with CpG, R484 or poly(I:C) alone and in combination with GM-CSF. CCL22-levels in a number of organs were analyzed.ResultsAnalyzing the different immune cell compartments in vitro, we found that DCs in whole splenocytes secrete CCL22 during culture while DC cultured alone showed no CCL22 secretion. When treated with CpG, CCL22-levels were reduced in splenocytes, while it was induced in DC culture alone. The same results were seen when RAG splenocytes, that lack functional B and T cells, were cultured with CpG. CpG treated B cells were able to suppress CCL22 secretion by DC unlike T cells alone. Co-cultures of T and B cells treated with CpG, however, induced the strongest CCL22 suppression in DC. In vivo, we could show that all TLR ligands tested reduced CCL22 in a number of organs significantly. Furthermore, CpG showed the strongest suppression of CCL22 even in the presence of the CCL22 inducer GM-CSF.5ConclusionsWe could show that B cells with T cells mediate CCL22 suppression by TLR ligands. The fact that CpG was able to reduce CCL22 levels even in the presence of the inducer GM-CSF demonstrates the potent CCL22 suppressive capacity of TLR ligands.ReferencesO’Neill LA, et al. The history of toll-like receptors – redefining innate immunity. Nat Rev Immunol 2013;13(6):453–60.Rothenfusser S, et al. Recent advances in immunostimulatory CpG oligonucleotides. Curr Opin Mol Ther 2003;5(2):98–106.Wang S, et al. Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells. Proc Natl Acad Sci U S A 2016;113(46): E7240–E7249.Rapp M, et al. CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes. J Exp Med 2019;216(5):1170–1181.Piseddu I, et al. Constitutive expression of CCL22 is mediated by T cell-derived GM-CSF. J Immunol 2020;205(8):2056–2065.Anz D, et al. Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer Res 2015;75(21):4483–93.Disclosure InformationJ. Grün: None. I. Piseddu: None. C. Perleberg: None. N. Röhrle: None. S. Endres: None. D. Anz: None.

scholarly journals Differential uptake of three clinically relevant allergens by human plasmacytoid dendritic cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Noelle Zurmühl ◽  
Anna Schmitt ◽  
Ulrike Formentini ◽  
Johannes Weiss ◽  
Heike Appel ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Healthy Subjects ◽  
Time Course ◽  
In Vitro Study ◽  
Allergic Diseases ◽  
Plasmacytoid Dendritic Cells ◽  
Antigen Uptake ◽  
Der P 1 ◽  
The Impact

Abstract Background Human plasmacytoid dendritic cells (pDC) have a dual role as interferon-producing and antigen-presenting cells. Their relevance for allergic diseases is controversial. and the impact of pDC on allergic immune responses is poorly understood. Methods This in vitro study on human pDC isolated from peripheral blood was designed to compare side by side the uptake of three clinically relevant representative allergens: fluorochrome-labeled house dust mite Der p 1, Bee venom extract from Apis mellifera (Api) and the food allergen OVA analyzed flow cytometry and confocal microscopy. Results We found that the internalization and its regulation by TLR9 ligation was significantly different between allergens in terms of time course and strength of uptake. Api and OVA uptake in pDC of healthy subjects was faster and reached higher levels than Der p 1 uptake. CpG ODN 2006 suppressed OVA uptake and to a lesser extent Der p 1, while Api internalization was not affected. All allergens colocalized with LAMP1 and EEA1, with Api being internalized particularly fast and reaching highest intracellular levels in pDC. Of note, we could not determine any specific differences in antigen uptake in allergic compared with healthy subjects. Conclusions To our knowledge this is the first study that directly compares uptake regulation of clinically relevant inhalative, injective and food allergens in pDC. Our findings may help to explain differences in the onset and severity of allergic reactions as well as in the efficiency of AIT.

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