scholarly journals Bone marrow mesenchymal stem cell-derived exosomes attenuate the maturation of dendritic cells and reduce the rejection of allogeneic skin transplantation in mice model

2021 ◽  
Author(s):  
RENLI ZHAO ◽  
Guohua Lai ◽  
Zhiwei Deng ◽  
Weida Zhuang ◽  
Mingjie Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Skin Transplantation ◽  
Skin Allograft ◽  
Transplant Tolerance ◽  
Bone Mesenchymal Stem Cells ◽  
Expression Levels ◽  
Indoleamine 2,3 Dioxygenase

Abstract Background Bone mesenchymal stem cells (BMSCs)-derived exosomes (B-exos) are attractive for applications in enabling alloantigen tolerance. An in-depth mechanistic understanding of the interaction between B-exos and dendritic cells (DCs) could lead to novel cell-based therapies for allogeneic transplantation. Herein, the potential of a B-exos-based application combined with DCs was explored for inducing allogeneic transplant tolerance. Methods After mixed culture of BMSCs and DCs for 48 hours, DCs from the upper layer were collected to analyze the expression levels of surface markers and mRNAs of inflammation-related cytokines. Then the DCs were co-cultured with B-exo before being collected to detect the mRNA and protein expression levels of indoleamine 2,3-dioxygenase (IDO). The treated DCs from different groups were co-cultured with naïve CD4 + T cells from the mouse spleen. The proliferation of CD4 + T cells and the proportion of CD4 + CD25 + Foxp3 + T cells were analyzed. Finally, the skins of BALB/c mice were transplanted to the back of C57 mice to establish a mouse allogeneic skin transplantation model. Results The coculture of DCs with BMSCs in a trans-well system downregulated the expression of the major histocompatibility complex class II (MHC-II) and CD80/86 costimulatory molecules on DCs, as well as the mRNA expression of interleukin-10 (IL-10), IL-12, and transforming growth factor-β (TGF-β). However, these findings were abolished when treated with GW4869. Moreover, B-exos (5 µg/mL) increased the expression of indoleamine 2,3-dioxygenase (IDO) in DCs treated with lipopolysaccharide (LPS) compared to the control cells. CD4 + CD25 + Foxp3 + T cells increased when cultured with B-exos-exposed DCs, which was attenuated by 1-methyl tryptophan (1MT). Mice recipients injected with B-exos-treated DCs significantly prolonged the skin allograft survival. The allografts showed slight cell infiltration and significantly preserved graft structure. Also, the level of CD4 + CD25 + Foxp3 + T cells was significantly higher in B-exos-exposed DCs recipient animals than that in other groups. Conclusions Taken together, these data suggested that the B-exos suppress the maturation of DCs and increase the expression of IDO, which might shed light on the role of B-exos in inducing alloantigen tolerance.

scholarly journals Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

2017 ◽  
Vol 114 (5) ◽  
pp. 1099-1104 ◽  
Author(s):  
William Bracamonte-Baran ◽  
Jonathan Florentin ◽  
Ying Zhou ◽  
Ewa Jankowska-Gan ◽  
W. John Haynes ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Extracellular Vesicle ◽  
Membrane Microdomains ◽  
Transplant Tolerance ◽  
Split Tolerance ◽  
Cross Dressing

Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; “cross-dressing”) of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a “split tolerance” status in mAAQ+mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC–specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1–dependent anergy in mAAQ+hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.

scholarly journals O31 IL-27 regulates the magnitude of ectopic germinal centres in experimental sialadenitis but fails to modulate IL-17 and IFNg production in CD4 T cells from patients with Sjögren's syndrome

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Davide Lucchesi ◽  
Rachel Coleby ◽  
Elena Pontarini ◽  
Edoardo Prediletto ◽  
Felice Rivellese ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Sjögren’S Syndrome ◽  
Cd4 T Cells ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Expression Levels ◽  
Cellular Source ◽  
Sjögren‘S Syndrome

Abstract Background A third of Sjögren’s syndrome (SS) patients develop ectopic lymphoid structures (ELS) in their salivary glands (SG). ELS play an active role in autoimmunity and contribute to the development of MALT lymphoma. Interleukin 27 (IL-27) exerts key immunomodulatory actions on numerous immune cells but its role in the formation and regulation of ELS in the SG of SS is unknown. Here we used a murine model of SG ELS to elucidate the role of IL-27 and its interaction with IL-17 in the development, regulation and function of ELS. We extended our observations on a cohort of SS patients to identify IL-27 cellular source, target cells and functional properties in modulating CD4 T cells function. Methods A single dose of reporter-encoding adenovirus was delivered directly to the SG of wild-type (WT) and IL-27RA-deficient (KO) mice to trigger ELS formation. For IL-17 blockade, anti-mouse IL-17A antibody was used. ELS development and peripheral immune responses were tracked by immuno-histopathology, FACS, and qPCR. Minor SG biopsies were collected from SS and non-specific sialadenitis (sicca) patients. Peripheral blood mononuclear cells (PBMC) isolated from SS and rheumatoid arthritis (RA) patients and age/sex-matched healthy donors (HD). For in vitro experiments PBMCs were incubated with IL-27 and analysed by FACS and cytokines levels were measured in culture supernatants. Tissue IL-27 was assessed by multicolour immunofluorescence. Results In WT mice, SG ELS formation was preceded by upregulation of IL-27p28 and infiltration of IL-27 producing cells. KO mice displayed larger, more abundant ELS in the SG. Higher expression levels of ELS-related genes (Cxcl13, Ccl19, Ltb, Aid) compared to WT mice were measured. KO mice showed an uncontrolled SG Th17 response and systemic IL-17A blockade caused a reduction in ELS size and in the expression of ELS-related genes. In SS patients SG and serum, we observed higher expression levels of IL-27 transcripts and protein, compared to sicca. SG IL-27 was selectively increased in ELS+ patients. IL-27 staining was detected in the T cell-rich areas of SG ELS often co-localizing with DC-LAMP+ dendritic cells. While IL-27 was able to significantly downregulate IL-17 production in HD and RA, CD4 T cells from patients with SS failed to downregulate IL-17 but showed an aberrant IFNγ release upon IL-27 incubation. Conclusion The IL-27-mediated restriction of Th17 expansion plays a critical role in the regulation of germinal centre response. Both in murine inducible ELS and in patients with SS, dendritic cells appear as the main cellular source of IL-27. IL-27 consistently failed to downregulate IL-17 release in CD4 T cells from SS patients, albeit its expression was increased in the ELS+ subset of SS, suggesting that a profound dysregulation of the IL-27/IL-17 axis play an important role in ELS formation in this condition. Disclosures D. Lucchesi None. R. Coleby None. E. Pontarini None. E. Prediletto None. F. Rivellese None. D. Hill None. A. Derrac Soria None. S. Jones None. I. Humphreys None. N. Sutcliffe None. A. Tappuni None. C. Pitzalis None. G. Jones None. M. Bombardieri None.

scholarly journals Human anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jake W. Rhodes ◽  
Rachel A. Botting ◽  
Kirstie M. Bertram ◽  
Erica E. Vine ◽  
Hafsa Rana ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Pathogen Detection ◽  
Hiv Transmission ◽  
Sexual Transmission ◽  
Mononuclear Phagocytes ◽  
Target Cells ◽  
Epithelial Surface ◽  
Transmission Studies

AbstractTissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).

scholarly journals Splenic Stroma-Educated Regulatory Dendritic Cells Induce Apoptosis of Activated CD4 T Cells via Fas Ligand-Enhanced IFN-γ and Nitric Oxide

2011 ◽  
Vol 188 (3) ◽  
pp. 1168-1177 ◽  
Author(s):  
Xiongfei Xu ◽  
Hai Yi ◽  
Zhenhong Guo ◽  
Cheng Qian ◽  
Sheng Xia ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Fas Ligand ◽  
Ifn Γ ◽  
Regulatory Dendritic Cells
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