The immun function of dendritic cells in SFTS patients Liu, Jingwen; Chai, Zhengbin; Ma, Quanping ...
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy,
08/2024
Journal Article
Recenzirano
Severe fever with thrombocytopenia syndrome (SFTS) is a newly emerging infectious disease caused by a novel bunyavirus in which host immune system suppression is thought to be crucial in disease ...development. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) critical for initiation and orchestration of the immune response. And it have been suggested that functionally impaired DCs may mediate the suppression of host-specific T-cell immune responses and thus facilitate viral persistence and disease progression.This study was designed to improve the in vitro culture method for DCs and investigate the different immunologic functions of DCs between SFTS patients and healthy people.
All confirmed SFTS patients (N = 10) were recruited from the Jinan Infectious Diseases Hospital in 2019; routine laboratory parameters were collected. The frequencies, phenotypes were analyzed by flow cytometry. And the levels of 8 cytokines in the cell culture supernatant were detected by flow cytometry.
On day 8 of the incubation period, cells were harvested and analyzed by flow cytometry. There were significant differences in the rates of CD1a-, CD83-positive cells between SFTS patients and healthy people (all P < 0.05). The detection of 8 cytokines in the culture supernatant showed that the expressions of IFN-α and IFN-γ in the culture supernatant of DC cells in SFTS patients were lower than those in normal people (P < 0.05, P < 0.01).
The present results indicate that DCs may be functionally impaired in SFTS. A decreased level of circulating mDCs was closely correlated with SFTS progression.
Background
cDC1 is a subset of conventional DCs, whose most recognized function is cross-presentation to CD8
+
T cells. We conducted this study to investigate the number and location of cDC1s in ...various human kidney diseases as well as their correlation with clinico-pathological features and CD8
+
T cells.
Methods
We analyzed 135 kidney biopsies samples. Kidney diseases included: acute tubular necrosis (ATN), acute interstitial nephritis (AIN), proliferative glomerulonephritis (GN) (IgA nephropathy, lupus nephritis, pauci-immune GN, anti-GBM disease), non-proliferative GN (minimal change disease, membranous nephropathy) and diabetic nephropathy. Indirect immunofluorescence staining was used to quantify cDC1s, CD1c
+
DCs, and CD8
+
T cells.
Results
cDC1s were rarely present in normal kidneys. Their number increased significantly in ATN and proliferative GN, proportionally much more than CD1c
+
DCs. cDC1s were mainly found in the interstitium, except in lupus nephritis, pauci-immune GN and anti-GBM disease, where they were prominent in glomeruli and peri-glomerular regions. The number of cDC1s correlated with disease severity in ATN, number of crescents in pauci-immune GN, interstitial fibrosis in IgA nephropathy and lupus nephritis, as well as prognosis in IgA nephropathy. The number of CD8
+
T cells also increased significantly in these conditions and cDC1 number correlated with CD8
+
T cell number in lupus nephritis and pauci-immune GN, with many of them closely co-localized.
Conclusions
cDC1 number correlated with various clinic-pathological features and prognosis reflecting a possible role in these conditions. Their association with CD8
+
T cells suggests a combined mechanism in keeping with the results in animal models.
Emerging evidence of immunological dysfunction have been described in endometriosis. Dendritic cells (DCs), one of the main antigen-presenting cells, are specialized in the initiation and modulation ...of the adaptive immune response. Emerging studies demonstrated both endometrial and circulating differences in DCs populations in women with endometriosis. However, the role and mechanism of peritoneal DCs in endometriosis is still unclear. The present study was undertaken to explore the features of peritoneal DCs in the pathogenesis of endometriosis. This study is beneficial to further clarify the cause of endometriosis and provide a new insight into the medical treatment for endometriosis.
The study included 12 women with endometriosis and 11 women without endometriosis. The C57BL6 mouse model of endometriosis was established by intraperitoneal injection of endometrial segments. The peritoneal DCs of endometriosis patients and mouse models were analyzed by fluorescence associated cell sorting (FACS) examination.
Increased cell density of peritoneal DCs were observed in endometriosis patients. Moreover, the proportion of mature DCs (mDCs, CD80
CD1a
cells) in the peritoneal DCs was lower whereas the proportion of immature DCs (iDCs, CD80
CD1a
cells) was increased in endometriosis patients. Similarly, the cell density of peritoneal DCs in murine models increased immediately after the injection of endometrial tissues and reached the highest level at 14 days. In addition, the proportion of mDCs (CD11c
CD80
cells) in the peritoneal DCs decreased immediately after the injection of endometrial tissues and then increased with the time until 42 days, but still lower than the control group. In contrast, the proportion of iDCs (CD11c
CD80
cells) in the peritoneal DCs showed the opposite dynamic changes. However, after treated with LPS, the mDCs proportion was significantly increased, leading to lower volume and weight of the endometriosis lesions.
Increased level of peritoneal DCs facilitated the pathogenesis of endometriosis lesions, especially in the early stage of the disease. Furthermore, peritoneal DCs maturation played an important role in the development of endometriosis.
Although nanoparticle vaccine is one of the promising therapeutic vaccines against cancers and many chronic infections, induction of strong and long-lasting antigen specific T cell response has still ...remained many challenges. A major challenge in achieving a robust CD8+ T cell response is the requirement of spatio-temporal orchestration of antigen cross-presentation in dendritic cells with innate stimulation. CD8α+ DCs are specialized for cross presentation and critical for cytotoxic T cell responses, which locate in the deeper paracortex of lymph nodes (LNs) in mice. However, due to size exclusion of compartmentalized network in LNs, nanoparticles with a radius of larger than 5 nm are difficult to access to the CD8α+ DCs. Here, we showed that polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles had an extensive contact with the resident CD8α+ DCs in LNs and delivered more OVA peptides than their free form to these DCs. Meanwhile, successfully delivering antigens into the CD8α+ DCs resulted in the increased cross presentation of antigens and the enhanced generation of effector CD8+ T cell. Our findings further demonstrated the critical role of CD8α+ DCs in cytotoxic T cell immunity in response to PEG-PE micelle-based vaccine, and also provided a valuable approach to generate T cell-mediated immune response.
Human primary dendritic cells (DCs) are heterogeneous by phenotype, function, and tissue localization and distinct from inflammatory monocyte-derived DCs. Current information regarding the ...susceptibility and functional role of primary human DC subsets to Mycobacterium tuberculosis (Mtb) infection is limited. Here, we dissect the response of different primary DC subsets to Mtb infection. Myeloid CD11c(+) cells and pDCs (C-type lectin 4C(+) cells) were located in human lymph nodes (LNs) of tuberculosis (TB) patients by histochemistry. Rare CD141(hi) DCs (C-type lectin 9A(+) cells) were also identified. Infection with live Mtb revealed a higher responsiveness of myeloid CD1c(+) DCs compared to CD141(hi) DCs and pDCs. CD1c(+) DCs produced interleukin (IL)-6, tumor necrosis factor α, and IL-1β but not IL-12p70, a cytokine important for Th1 activation and host defenses against Mtb. Yet, CD1c(+) DCs were able to activate autologous naïve CD4(+) T cells. By combining cell purification with fluorescence-activated cell sorting and gene expression profiling on rare cell populations, we detected in responding CD4(+) T cells, genes related to effector-cytolytic functions and transcription factors associated with Th1, Th17, and Treg polarization, suggesting multifunctional properties in our experimental conditions. Finally, immunohistologic analyses revealed contact between CD11c(+) cells and pDCs in LNs of TB patients and in vitro data suggest that cooperation between Mtb-infected CD1c(+) DCs and pDCs favors stimulation of CD4(+) T cells.
•TD-DCS brain detection is severely affected by present optoelectronic devices.•CW-DCS is currently still superior to TD-DCS in brain functional detection at 830 nm.•With advance of optoelectronics, ...TD-DCS detection ability can be enhanced.
Diffuse correlation spectroscopy (DCS) is an optical technique originally used for measuring dynamic properties of multiple scattering media. Depending on the type of light source used in the system, DCS can be classified as continuous wave DCS (CW-DCS) or time-domain DCS (TD-DCS). With pathlength-resolved measurement, TD-DCS can theoretically achieve a higher sensitivity detection than CW-DCS on dynamics in deep tissue. However, TD-DCS is affected by more factors than CW-DCS such as the instrument response function (IRF), finite coherence length of the light source (Lc), photon detection efficiency (Q), thus the detection ability in the application of measuring cerebral blood flow (CBF) may be degraded. To elucidate this, we used a simulation approach with a realistic head model to show the detection ability of the two DCS techniques on measuring the functional change in CBF with the same incident light wavelength (830 nm), incident light power (75 mW) and single mode detection fiber. The result reveals that TD-DCS is less sensitive than CW-DCS in detecting human brain function in the condition of available optoelectronic devices at 830 nm. This simulation work may also provide a solution to improve the detection ability of TD-DCS on human brain.
Glioblastoma (GBM) is the most aggressive type of glioma (Grade IV). The presence of cytotoxic T lymphocyte (CTLs) has been associated with improved outcomes in patients with GBM, and it is believed ...that the activation of CTLs by dendritic cells may play a critical role in controlling the growth of GBM. DCs are professional antigen-presenting cells (APC) that orchestrate innate and adaptive anti-GBM immunity. DCs can subsequently differentiate into plasmacytoid DCs (pDC), conventional DC1 (cDC1), conventional (cDC2), and monocyte-derived DCs (moDC) depending on environmental exposure. The different subsets of DCs exhibit varying functional capabilities in antigen presentation and T cell activation in producing an antitumor response. In this review, we focus on recent studies describing the phenotypic and functional characteristics of DC subsets in humans and their respective antitumor immunity and immunotolerance roles in the GBM-associated microenvironment. The critical components of crosstalk between DC subsets that contribute significantly to GBM-specific immune responses are also highlighted in this review with reference to the latest literature. Since DCs could be prime targets for therapeutic intervention, it is worth summarizing the relevance of DC subsets with respect to GBM-associated immunologic tolerance and their therapeutic potential.
Fig. 1. The heterogeneity of human DC subsets and potential crosstalk toward DC subsets within the GBM microenvironment.
(A) Surface markers of human pDCs are characterized by CD1c + CD123 + CD135 + CD303 + CD304+; human moDCs are characterized by CD34 + CD303 + CD304 + CCR7+; human DC1 is distinguished as CD11 + CD26 + CD70 + CD80 + CD86 + CD103 + CD141 + CLEC9A+, and cDC2 as CD1c + CD11 + CD40 + CD123 + CD172a + CD303 + ZEB2 + FLT3+. The process of tolerance in the GBM immunosuppressive microenvironment: Activated CD4+ T cells differentiate into Th2, Th17, and Treg cell subtypes. Th2 cells are characterized by transcription factors (STAT3, GATA3) as well as secreted cytokines (IL-4, IL-5, IL-10, IL-13, and IL-17). Th17 cells are characterized by transcription factors (STAT3, Roryt) as well as secreted cytokines (IL-17A/F, IL-10, and TGF-β). Treg cells are characterized by transcription factors (STAT5, Foxp3) as well as produced cytokines (IL-10, IL-35, and TGF-β). ARG1, nitric oxide (NO), and PGE2 are major contributors to MDSC immune suppressive activity.
(B) Complex interplay of human DC subsets in the GBM microenvironment: (1) pDCs promote the production of IFN-α/granzyme B/TRAIL to exert CD8+ T cell cytotoxic effects directly, while Treg/Th2 cells are generated through immunosuppressive factors, such as IDO, OX40L/OX40, and ICOSL/ICOS, hindering effective anti-GBM immunity; (2) Th1, Th17, and Treg cells are activated by moDCs. moDCs further promote CD8+ T cells to kill GBM cells via cross-presentation of GBM-associated antigens; (3) cDC1 cells play a critical role in the crosstalk with Th1 or CD8+ T cells. Th1 cells are characterized by transcription factors (STAT4, T-bet) as well as secreted cytokines (IFN-γ, IL-2, and TNF-a). CD8+ T cells are activated to exert cytotoxic effects. XCL1 and CCL3/4 are produced from activated CD8 T cells, further recruiting cDC1 and pDC to elicit activation of maximal immune responses against GBM; (4) cDC2 cells mainly target CD4 T cells via MHC II. Th1, Th2, and Th17 cells are also activated by moDCs. Stimulating or promoting effects are displayed as red arrows, and inhibiting interactions are presented as flat green arrowheads. Display omitted
•the phenotypic and functional characteristics of DC subsets in humans.•The respective antitumor immunity of DC subsets and immunotolerance roles in the GBM-associated microenvironment.•The critical components of crosstalk between DC subsets that contribute significantly to GBM-specific immune responses.
Allergic contact dermatitis (ACD) is a complex skin pathology occurring in reaction against environmental substances found in the workplace (cement, hair dyes, textile dyes), in the private ...environment (e.g., household products, cosmetic ingredients), or following skin exposure to drugs. Many cells are involved in the initiation of ACD during the sensitization phase. The four key events (KE) of skin sensitization AOP are covalent binding to skin proteins (KE1), keratinocyte activation (KE2), activation of DCs (KE3), and T-cell activation and proliferation (KE4), leading to the adverse outcome of ACD. Dendritic cells (DCs) are thus playing a key role in ACD pathophysiology. Indeed, in the presence of chemical sensitizers, DCs migrate from the skin to the draining lymph nodes and present peptide-chemical conjugates to T cells, leading to their activation and proliferation.
methods have been actively developed to assess the activation of DCs by chemicals to establish a reliable
sensitization test. Therefore, this review will detail the most used methods and protocols to develop DC models
. Three different models of DCs will be addressed: 1) DCs derived from Cord Blood (CD34-DCs), 2) DCs derived from Monocytes (Mo-DCs), and 3) DCs derived from mice Bone-Marrow (BM-DCs). In addition, a model of exposition to contact sensitizers to assess KE3 of skin sensitization will be detailed for each of the models presented.
The contribution of cross-presenting XCR1+ dendritic cells (DCs) and SIRPα+ DCs in maintaining T cell function during exhaustion and immunotherapeutic interventions of chronic infections remains ...poorly characterized. Using the mouse model of chronic LCMV infection, we found that XCR1+ DCs are more resistant to infection and highly activated compared with SIRPα+ DCs. Exploiting XCR1+ DCs via Flt3L-mediated expansion or XCR1-targeted vaccination notably reinvigorates CD8+ T cells and improves virus control. Upon PD-L1 blockade, XCR1+ DCs are not required for the proliferative burst of progenitor exhausted CD8+ T (TPEX) cells but are indispensable to sustain the functionality of exhausted CD8+ T (TEX) cells. Combining anti-PD-L1 therapy with increased frequency of XCR1+ DCs improves functionality of TPEX and TEX subsets, while increase of SIRPα+ DCs dampened their proliferation. Together, this demonstrates that XCR1+ DCs are crucial for the success of checkpoint inhibitor-based therapies through differential activation of exhausted CD8+ T cell subsets.
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•XCR1+ DCs are more functional and less prone to LCMV infection than SIRPα+ DCs•Expanding XCR1+ DCs via Flt3L or delivering XCR1-targeting Ag improve virus control•Anti-PD-L1 treatment increases XCR1+ DC numbers and IL-12 production•XCR1+ DCs promote TEX functionality but are dispensable for TPEX proliferation burst
Domenjo-Vila et al. show that XCR1+ DCs are crucial in augmenting exhausted CD8+ T cell effector functions during immunotherapeutic interventions in chronic virus infections. Increased T cell functionality leads to reduced virus loads. XCR1+ DCs should be among the preferential targets in immunotherapeutic cure strategies.
Throughout the last decades, dendritic cell (DC)-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex ...vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations for their lack of robustness. Therefore, a great effort has been made to identify DC subsets with superior features for the establishment of effective anti-tumor responses and to apply them in therapeutic approaches. Among characterized human DC subpopulations, conventional type 1 DCs (cDC1) have emerged as a highly desirable tool for empowering anti-tumor immunity. This DC subset excels in its capacity to prime antigen-specific cytotoxic T cells and to activate natural killer (NK) and natural killer T (NKT) cells, which are critical factors for an effective anti-tumor immune response. Here, we sought to revise the immunobiology of cDC1 from their ontogeny to their development, regulation and heterogeneity. We also address the role of this functionally thrilling DC subset in anti-tumor immune responses and the most recent efforts to apply it in cancer immunotherapy.
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