Critical Role of the Tumor Suppressor Tuberous Sclerosis Complex 1 in Dendritic Cell Activation of CD4 T Cells by Promoting MHC Class II Expression via IRF4 and CIITA

Abstract IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) are members of the IL-1 family of cytokines. These cytokines bind to IL-36R (IL-1Rrp2) and IL-1RAcP, activating similar intracellular signals as IL-1, whereas IL-36Ra (IL-1F5) acts as an IL-36R antagonist (IL-36Ra). In this study, we show that both murine bone marrow-derived dendritic cells (BMDCs) and CD4+ T lymphocytes constitutively express IL-36R and respond to IL-36α, IL-36β, and IL-36γ. IL-36 induced the production of proinflammatory cytokines, including IL-12, IL-1β, IL-6, TNF-α, and IL-23 by BMDCs with a more potent stimulatory effect than that of other IL-1 cytokines. In addition, IL-36β enhanced the expression of CD80, CD86, and MHC class II by BMDCs. IL-36 also induced the production of IFN-γ, IL-4, and IL-17 by CD4+ T cells and cultured splenocytes. These stimulatory effects were antagonized by IL-36Ra when used in 100- to 1000-fold molar excess. The immunization of mice with IL-36β significantly and specifically promoted Th1 responses. Our data thus indicate a critical role of IL-36R ligands in the interface between innate and adaptive immunity, leading to the stimulation of T helper responses.

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Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation

The Journal of Immunology ◽

10.4049/jimmunol.180.6.3782 ◽

2008 ◽

Vol 180 (6) ◽

pp. 3782-3788 ◽

Cited By ~ 7

Author(s):

Chiara Casati ◽

Chiara Camisaschi ◽

Luisa Novellino ◽

Arabella Mazzocchi ◽

Frédéric Triebel ◽

...

Keyword(s):

T Cells ◽

Dendritic Cell ◽

Human Lymphocyte ◽

Cell Activation ◽

Lymphocyte Activation ◽

Dendritic Cell Activation ◽

Activated T Cells ◽

Lymphocyte Activation Gene

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Protective role of (5R)-5-hydroxytriptolide in lipopolysaccharide-induced acute lung injury by suppressing dendritic cell activation

International Immunopharmacology ◽

10.1016/j.intimp.2021.108410 ◽

2021 ◽

pp. 108410

Author(s):

Yao Chen ◽

Zhongshu Kuang ◽

Wei Wei ◽

Yanyan Hu ◽

Sucheng Mu ◽

...

Keyword(s):

Acute Lung Injury ◽

Dendritic Cell ◽

Lung Injury ◽

Cell Activation ◽

Protective Role ◽

Dendritic Cell Activation

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Dendritic Cell Activation Prevents MHC Class II Ubiquitination and Promotes MHC Class II Survival Regardless of the Activation Stimulus

Journal of Biological Chemistry ◽

10.1074/jbc.m110.157586 ◽

2010 ◽

Vol 285 (53) ◽

pp. 41749-41754 ◽

Cited By ~ 35

Author(s):

Even Walseng ◽

Kazuyuki Furuta ◽

Romina S. Goldszmid ◽

Karis A. Weih ◽

Alan Sher ◽

...

Keyword(s):

Dendritic Cell ◽

Mhc Class Ii ◽

Cell Activation ◽

Class Ii ◽

Dendritic Cell Activation

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

Blood ◽

10.1182/blood.v126.23.658.658 ◽

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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Toll-like Receptor 9–Dependent and –Independent Dendritic Cell Activation by Chromatin–Immunoglobulin G Complexes

Journal of Experimental Medicine ◽

10.1084/jem.20031942 ◽

2004 ◽

Vol 199 (12) ◽

pp. 1631-1640 ◽

Cited By ~ 390

Author(s):

Melissa W. Boulé ◽

Courtney Broughton ◽

Fabienne Mackay ◽

Shizuo Akira ◽

Ann Marshak-Rothstein ◽

...

Keyword(s):

Dendritic Cell ◽

Lupus Erythematosus ◽

Immune Complexes ◽

Cell Activation ◽

Critical Role ◽

Adaptive Immune Response ◽

Foreign Protein ◽

Interleukin 12 ◽

Toll Like Receptor ◽

Dendritic Cell Activation

Dendritic cell (DC) activation by nucleic acid–containing immunoglobulin (Ig)G complexes has been implicated in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms responsible for activation and subsequent disease induction are not completely understood. Here we show that murine DCs are much more effectively activated by immune complexes that contain IgG bound to chromatin than by immune complexes that contain foreign protein. Activation by these chromatin immune complexes occurs by two distinct pathways. One pathway involves dual engagement of the Fc receptor FcγRIII and Toll-like receptor (TLR)9, whereas the other is TLR9 independent. Furthermore, there is a characteristic cytokine profile elicited by the chromatin immune complexes that distinguishes this response from that of conventional TLR ligands, notably the induction of BAFF and the lack of induction of interleukin 12. The data establish a critical role for self-antigen in DC activation and explain how the innate immune system might drive the adaptive immune response in SLE.

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