scholarly journals MARCH1 protects the lipid raft and tetraspanin web from MHCII proteotoxicity in dendritic cells

2018 ◽  
Vol 217 (4) ◽  
pp. 1395-1410 ◽  
Author(s):  
Jaehak Oh ◽  
Justin S.A. Perry ◽  
Heather Pua ◽  
Nicole Irgens-Möller ◽  
Satoshi Ishido ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lipid Rafts ◽  
Treg Cell ◽  
Substantial Reduction ◽  
Underlying Mechanism ◽  
Treg Cells ◽  
Membrane Domains ◽  
Significant Impairment ◽  
Quality Control Mechanism ◽  
Antigen Presenting

Dendritic cells (DCs) produce major histocompatibility complex II (MHCII) in large amounts to function as professional antigen presenting cells. Paradoxically, DCs also ubiquitinate and degrade MHCII in a constitutive manner. Mice deficient in the MHCII-ubiquitinating enzyme membrane-anchored RING-CH1, or the ubiquitin-acceptor lysine of MHCII, exhibit a substantial reduction in the number of regulatory T (Treg) cells, but the underlying mechanism was unclear. Here we report that ubiquitin-dependent MHCII turnover is critical to maintain homeostasis of lipid rafts and the tetraspanin web in DCs. Lack of MHCII ubiquitination results in the accumulation of excessive quantities of MHCII in the plasma membrane, and the resulting disruption to lipid rafts and the tetraspanin web leads to significant impairment in the ability of DCs to engage and activate thymocytes for Treg cell differentiation. Thus, ubiquitin-dependent MHCII turnover represents a novel quality-control mechanism by which DCs maintain homeostasis of membrane domains that support DC’s Treg cell–selecting function.

scholarly journals Foxp3+ CD4+ regulatory T cells control dendritic cells in inducing antigen-specific immunity to emerging SARS-CoV-2 antigens

2021 ◽  
Vol 17 (12) ◽  
pp. e1010085
Author(s):  
Ryuta Uraki ◽  
Masaki Imai ◽  
Mutsumi Ito ◽  
Hiroaki Shime ◽  
Mizuyu Odanaka ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Treg Cell ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Cell Depletion ◽  
Humoral And Cellular Immunity ◽  
Specific Immunity ◽  
Antigen Presenting

Regulatory T (Treg) cells, which constitute about 5–10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1). Notably, without the use of adjuvants, transient Treg-cell depletion in mice induced anti-S1 antibodies that neutralized authentic SARS-CoV-2, follicular helper T cell formation and S1-binding germinal center B cell responses, but prevented the onset of developing autoimmune diseases. To further clarify the mechanisms, we investigated maturation of dendritic cells (DCs), which is essential to initiate antigen-specific immunity. We found that the transient Treg-cell depletion resulted in maturation of both migratory and resident DCs in draining lymph nodes that captured S1-antigen. Moreover, we observed S1-specific CD4+ T cells and CD8+ T cells with interferon-γ production. Thus, captured S1 was successfully presented by DCs, including cross-presentation to CD8+ T cells. These data indicate that transient Treg-cell depletion in the absence of adjuvants induces maturation of antigen-presenting DCs and succeeds in generating antigen-specific humoral and cellular immunity against emerging SARS-CoV-2 antigens. Finally, we showed that SARS-CoV-2 antigen-specific immune responses induced by transient Treg-cell depletion in the absence of adjuvants were compatible with those induced with an effective adjuvant, polyriboinosinic:polyribocytidyl acid (poly IC) and that the combination of transient Treg-cell depletion with poly IC induced potent responses. These findings highlight the capacity for manipulating Treg cells to induce protective adaptive immunity to SARS-CoV-2 with activating antigen-presenting DCs, which may improve the efficacy of ongoing vaccine therapies and help enhance responses to emerging SARS-CoV-2 variants.

Regulatory T Cell Development

2020 ◽  
Vol 38 (1) ◽  
pp. 421-453 ◽  
Author(s):  
Peter A. Savage ◽  
David E.J. Klawon ◽  
Christine H. Miller
Keyword(s):  
Treg Cell ◽  
Current Knowledge ◽  
T Cell Development ◽  
Cell Types ◽  
Treg Cells ◽  
Cell Development ◽  
Clear Understanding ◽  
Major Barrier ◽  
Health And Disease ◽  
Antigen Presenting

Foxp3-expressing CD4+ regulatory T (Treg) cells play key roles in the prevention of autoimmunity and the maintenance of immune homeostasis and represent a major barrier to the induction of robust antitumor immune responses. Thus, a clear understanding of the mechanisms coordinating Treg cell differentiation is crucial for understanding numerous facets of health and disease and for developing approaches to modulate Treg cells for clinical benefit. Here, we discuss current knowledge of the signals that coordinate Treg cell development, the antigen-presenting cell types that direct Treg cell selection, and the nature of endogenous Treg cell ligands, focusing on evidence from studies in mice. We also highlight recent advances in this area and identify key unanswered questions.

scholarly journals Tumor-derived extracellular vesicles regulate tumor-infiltrating regulatory T cells via the inhibitory immunoreceptor CD300a

2020 ◽  
Author(s):  
Yuta Nakazawa ◽  
Kazumasa Kanemaru ◽  
Chigusa Nakahashi-Oda ◽  
Akira Shibuya
Keyword(s):  
Dendritic Cells ◽  
Treg Cell ◽  
Cell Activation ◽  
Extracellular Vesicle ◽  
Treg Cells ◽  
Wild Type ◽  
Cell Numbers ◽  
Tumor Microenvironments ◽  
Deficient Mice

AbstractAlthough tumor-infiltrating regulatory T (Treg) cells play a pivotal role in tumor immunity, how Treg cell activation are regulated in tumor microenvironments remains unclear. Here, we found that mice deficient in the inhibitory immunoreceptor CD300a on their dendritic cells (DCs) have increased numbers of Treg cells in tumors and greater tumor growth compared with wild-type mice after transplantation of B16 melanoma. Pharmacological impairment of extracellular vesicle (EV) release decreased Treg cell numbers in CD300a-deficient mice. Coculture of DCs with tumor-derived EV (TEV) induced the internalization of CD300a and the incorporation of EVs into endosomes, in which CD300a inhibited TEV-mediated TLR3-TRIF signaling for activation of the IFN-β-Treg cells axis. We also show that higher expression of CD300A was associated with decreased tumor-infiltrating Treg cells and longer survival time in patients with melanoma. Our findings reveal the role of TEV and CD300a on DCs in Treg cell activation in the tumor microenvironment.

scholarly journals Alterations of Dendritic Cells in Sepsis: Featured Role in Immunoparalysis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Xia Fan ◽  
Zheng Liu ◽  
He Jin ◽  
Jun Yan ◽  
Hua-ping Liang
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Immune Disorder ◽  
And Function ◽  
Antigen Presenting

Sepsis, the leading cause of mortality in intensive care unit, is characterized by hyperinflammatory response in the early stage and followed by a period of immunosuppression. This immune disorder is believed to be the potent factor that is tightly associated with high mortality in sepsis. Dendritic cells (DCs) serve as professional antigen-presenting cells that play a vital role in immune response by activating T lymphocytes. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Therefore, a better understanding of the DCs pathology will be undoubtedly beneficial for resolving the problems occurring in sepsis. This review discusses effects of sepsis on DCs number and function, including surface molecules expression, cytokines secretion, and T cell activation, and the underlying mechanism as well as some potential therapeutic strategies.

scholarly journals Functional Ambivalence of Dendritic Cells: Tolerogenicity and Immunogenicity

2021 ◽  
Vol 22 (9) ◽  
pp. 4430
Author(s):  
Ji-Hee Nam ◽  
Jun-Ho Lee ◽  
So-Yeon Choi ◽  
Nam-Chul Jung ◽  
Jie-Young Song ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inflammatory Diseases ◽  
Immunosuppressive Agents ◽  
Treg Cells ◽  
Peripheral Tolerance ◽  
Cell Mediated Immunity ◽  
Antigen Presenting

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and inducers of T cell-mediated immunity. Although DCs play a central role in promoting adaptive immune responses against growing tumors, they also establish and maintain peripheral tolerance. DC activity depends on the method of induction and/or the presence of immunosuppressive agents. Tolerogenic dendritic cells (tDCs) induce immune tolerance by activating CD4+CD25+Foxp3+ regulatory T (Treg) cells and/or by producing cytokines that inhibit T cell activation. These findings suggest that tDCs may be an effective treatment for autoimmune diseases, inflammatory diseases, and infertility.

scholarly journals Tumor-derived extracellular vesicles regulate tumor-infiltrating regulatory T cells via the inhibitory immunoreceptor CD300a

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yuta Nakazawa ◽  
Nanako Nishiyama ◽  
Hitoshi Koizumi ◽  
Kazumasa Kanemaru ◽  
Chigusa Nakahashi-Oda ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Treg Cell ◽  
Cell Activation ◽  
Extracellular Vesicle ◽  
Treg Cells ◽  
Wild Type ◽  
Cell Numbers ◽  
Tumor Microenvironments ◽  
Deficient Mice

Although tumor-infiltrating regulatory T (Treg) cells play a pivotal role in tumor immunity, how Treg cell activation are regulated in tumor microenvironments remains unclear. Here, we found that mice deficient in the inhibitory immunoreceptor CD300a on their dendritic cells (DCs) have increased numbers of Treg cells in tumors and greater tumor growth compared with wild-type mice after transplantation of B16 melanoma. Pharmacological impairment of extracellular vesicle (EV) release decreased Treg cell numbers in CD300a-deficient mice. Coculture of DCs with tumor-derived EV (TEV) induced the internalization of CD300a and the incorporation of EVs into endosomes, in which CD300a inhibited TEV-mediated TLR3–TRIF signaling for activation of the IFN-β-Treg cells axis. We also show that higher expression of CD300A was associated with decreased tumor-infiltrating Treg cells and longer survival time in patients with melanoma. Our findings reveal the role of TEV and CD300a on DCs in Treg cell activation in the tumor microenvironment.

Immunosuppressant Sinomenine Promotes Differentiation of Bone Marrow Progenitors to IL-10-Producing Ialow Regulatory Dendritic Cells Leading to the Prolongation of Allograft Survival.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4872-4872
Author(s):  
Quanxing Wang ◽  
Jianchun Wu ◽  
Jianli Wang ◽  
Yushan Liu ◽  
Guoyou Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Treg Cells ◽  
Dependent Manner ◽  
Allograft Survival ◽  
Antigen Presenting

Abstract Sinomenine (SN), an immunosuppressive compound derived from the Chinese medicinal plant Sinomenium acutum, effectively inhibits both proinflammatory factor production and lymphocyte proliferation. However, the effects of SN on dendritic cells (DC), the professional antigen-presenting cells, have not been elucidated. In this study, we examined the effects of SN on DC generation, maturation and function. We found that SN affected DC in a dose dependent manner; significantly inhibiting surface expression of MHC class II, CD86, and CD40, production of IL-12, TNF-a, IL-1b, and T cell-allostimulatory activity. SN targets antigen-presenting capacity of DC not only via the MHC class II pathway, but also impairs DC migration by inhibiting LPS-induced up-regulation of CCR7 and CXCR4 expression. These inhibitory effects on DC may be partially due to SN-mediated suppression of NF-kB and p38 MAPK pathways. Further study showed that SN-treated DC (DC-SN) induce donor-specific T cell hyporesponsiveness and trigger generation of IL-10-producing T regulatory-like cells in vitro. In vivo transplant studies revealed that, compared to pretreatment with immature DC, pretreatment of recipients with DC-SN could significantly prolong allograft survival, although long-term allograft acceptance was not achieved. Importantly, pretreatment of recipients with DC-SN in combination with SN administration profoundly prolonged allograft survival, resulting in long-term survival of 30% of allografts. Increased generation of CD4+CD25+ Treg cells and enhanced microchimerism in recipients brought on by combination treatment may contribute to this extension of allograft lifespan. Our results demonstrate that SN can promote bone marrow progenitors differentiation to IL-10-producing (Ialow) regulatory DC which contribute to induction of tolerance by increase generation of Treg cells.

scholarly journals Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27–CD70 pathway

2013 ◽  
Vol 210 (4) ◽  
pp. 715-728 ◽  
Author(s):  
Jonathan M. Coquet ◽  
Julie C. Ribot ◽  
Nikolina Bąbała ◽  
Sabine Middendorp ◽  
Gerda van der Horst ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Treg Cell ◽  
Treg Cells ◽  
Cell Development ◽  
Cell Generation ◽  
Thymic Epithelial Cells ◽  
Clonal Deletion ◽  
Cell Numbers ◽  
Thymic Medulla

CD4+Foxp3+ regulatory T cells (Treg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27–CD70 co-stimulation in the thymus rescues developing Treg cells from apoptosis and thereby promotes Treg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced Treg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4+Foxp3− T cell numbers. The CD27–CD70 pathway was not required for pre-Treg cell generation, Foxp3 induction, or mature Treg cell function. Rather, CD27 signaling enhanced positive selection of Treg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic Treg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire− and Aire+ medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to Treg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α+ subset of thymic DCs promoted Treg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27–CD70 co-stimulation rescues developing Treg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.

scholarly journals Spatial Distribution and Predictive Significance of Dendritic Cells and Macrophages in Esophageal Cancer Treated With Combined Chemoradiotherapy and PD-1 Blockade

2022 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxue Ma ◽  
Zhoubo Guo ◽  
Xiaoying Wei ◽  
Gang Zhao ◽  
Dong Han ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Spatial Distribution ◽  
Tumor Cells ◽  
Combination Treatment ◽  
Locally Advanced ◽  
Underlying Mechanism ◽  
Stromal Compartment ◽  
Mutation Burden ◽  
Antigen Presenting ◽  
Tumor Biopsies

BackgroundThe first clinical study (NCT03671265) of first-line chemoradiotherapy combined with PD-1 blockade showed promising treatment outcomes in locally advanced esophageal squamous cell carcinoma (ESCC). However, partial patients did not respond to the combination treatment. The roles of dendritic cells (DCs) and macrophages in this combination treatment remain poorly understood.MethodsWe performed multiplexed immunofluorescence method to identify CD11c+ DCs, CD68+ macrophages, and their PD-L1- or PD-L1+ subpopulations in paired tumor biopsies (n = 36) collected at baseline and during the combination treatment (after radiation, 40 Gy) from the phase Ib trial (NCT03671265). We applied whole exome sequencing in the baseline tumor biopsies (n = 14) to estimate tumor mutation burden (TMB). We dynamically investigated the spatial distribution of DCs and macrophages under chemoradiotherapy combined with PD-1 blockade, and evaluated the association between their spatial distribution and combination outcome, and TMB.ResultsThe results showed that high percentages of PD-L1- DCs and macrophages in the baseline tumor compartment, but not in the stromal compartment, predicted improved OS and PFS. Chemoradiotherapy combined with PD-1 blockade promoted DCs and macrophages to migrate closer to tumor cells. During combination treatment, PD-L1- tumor cells were nearest to PD-L1- DCs and macrophages, while PD-L1+ tumor cells were next to PD-L1+ DCs and macrophages. High TMB was closely associated with a shorter distance from tumor cells to DCs and macrophages. Shorter distance between PD-L1+ tumor cells and PD-L1+ DCs or PD-L1- macrophages during the combination was correlated with better OS. Shorter distance between PD-L1- tumor cells and PD-L1- macrophages during combination was associated with both longer OS and PFS.ConclusionsPD-L1- or PD-L1+ DCs and macrophages exhibit distinct spatial distribution in ESCC. The close distance between tumor cells and these antigen-presenting cells (APCs) is critical to the clinical outcome in chemoradiotherapy combined with PD-1 blockade in ESCC patients. Our results highlight the predictive potential of spatial patterns of APCs in chemoradiotherapy combined with immunotherapy and reveal the underlying mechanism of APCs participating in chemoradiotherapy-induced antitumor immune response in ESCC.

scholarly journals Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance

2013 ◽  
Vol 210 (4) ◽  
pp. 775-788 ◽  
Author(s):  
Pejman Soroosh ◽  
Taylor A. Doherty ◽  
Wei Duan ◽  
Amit Kumar Mehta ◽  
Heonsik Choi ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Lung Inflammation ◽  
Treg Cells ◽  
Cell Induction ◽  
Plasmacytoid Dcs ◽  
Antigen Presenting ◽  
Regulatory Functions ◽  
Cell Deletion

Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3+ iTreg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3+ Treg cells. Treg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma.

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