CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10–driven MARCH1-mediated ubiquitination and degradation

Effective vaccine adjuvants must induce expression of major histocompatability (MHC) class II proteins and the costimulatory molecule CD86 on dendritic cells (DCs). However, some adjuvants elicit production of cytokines resulting in adverse inflammatory consequences. Development of agents that selectively increase MHC class II and CD86 expression without triggering unwanted cytokine production requires a better understanding of the molecular mechanisms influencing the production and degradation of MHC class II and CD86 in DCs. Here, we investigate how CD83, an immunoglobulin protein expressed on the surface of mature DCs, promotes MHC class II and CD86 expression. Using mice with an N-ethyl-N-nitrosourea–induced mutation eliminating the transmembrane (TM) region of CD83, we found that the TM domain of CD83 enhances MHC class II and CD86 expression by blocking MHC class II association with the ubiquitin ligase MARCH1. The TM region of CD83 blocks interleukin 10–driven, MARCH1-dependent ubiquitination and degradation of MHC class II and CD86 in DCs. Exploiting this posttranslational pathway for boosting MHC class II and CD86 expression on DCs may provide an opportunity to enhance the immunogenicity of vaccines.

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Activation of Human Dendritic Cells Is Modulated by Components of the Outer Membranes of Neisseria meningitidis

Infection and Immunity ◽

10.1128/iai.71.10.5590-5597.2003 ◽

2003 ◽

Vol 71 (10) ◽

pp. 5590-5597 ◽

Cited By ~ 21

Author(s):

Tamara Al-Bader ◽

Myron Christodoulides ◽

John E. Heckels ◽

Judith Holloway ◽

Amanda E. Semper ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Neisseria Meningitidis ◽

Mrna Expression ◽

Mhc Class Ii ◽

Human Monocyte ◽

Class Ii ◽

Effective Vaccine ◽

Tlr4 Mrna ◽

Mhc Class Ii Molecules

ABSTRACT Neisseria meningitidis serogroup B is a major cause of life-threatening meningitis and septicemia worldwide, and no effective vaccine is available. Initiation of innate and acquired immune responses to N. meningitidis is likely to be dependent on cellular responses of dendritic cells (DC) to antigens present in the outer membrane (OM) of the meningococcus. In this study, the responses of human monocyte-derived DC (mo-DC) to OM isolated from parent (lipopolysaccharide [LPS]-replete) meningococci and from a mutant deficient in LPS were investigated. Parent OM selectively up-regulated Toll-like receptor 4 (TLR4) mRNA expression and induced mo-DC maturation, as reflected by increased production of chemokines, proinflammatory cytokines, and CD83, CD80, CD86, CD40, and major histocompatibility complex (MHC) class II molecules. In contrast, LPS-deficient OM selectively up-regulated TLR2 mRNA expression and induced moderate increases in both cytokine production and expression of CD86 and MHC class II molecules. Preexposure to OM, with or without LPS, augmented the allostimulatory properties of mo-DC, which induced proliferation of naive CD4+ CD45RA+ T cells. In addition, LPS-replete OM induced a greater gamma interferon/interleukin-13 ratio in naive T cells, whereas LPS-deficient OM induced the reverse profile. These data demonstrate that components of the OM, other than LPS, are also likely to be involved in determining the levels of DC activation and the nature of the T-helper immune response.

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Short Communication Low CD83, but Normal MHC Class II and Costimulatory Molecule Expression, on Spleen Dendritic Cells from HIV+Patients

AIDS Research and Human Retroviruses ◽

10.1089/aid.1998.14.505 ◽

1998 ◽

Vol 14 (6) ◽

pp. 505-513 ◽

Cited By ~ 25

Author(s):

DORIAN McILROY ◽

BRIGITTE AUTRAN ◽

JEAN-PIERRE CLAUVEL ◽

ERIC OKSENHENDLER ◽

PATRICE DEBRÉ ◽

...

Keyword(s):

Dendritic Cells ◽

Mhc Class Ii ◽

Short Communication ◽

Costimulatory Molecule ◽

Class Ii ◽

Hiv Patients

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The Trophic Life Cycle Stage of the Opportunistic Fungal Pathogen Pneumocystis murina Hinders the Ability of Dendritic Cells To Stimulate CD4+ T Cell Responses

Infection and Immunity ◽

10.1128/iai.00396-17 ◽

2017 ◽

Vol 85 (10) ◽

Cited By ~ 7

Author(s):

Heather M. Evans ◽

Andrew Simpson ◽

Shu Shen ◽

Arnold J. Stromberg ◽

Carol L. Pickett ◽

...

Keyword(s):

Dendritic Cells ◽

Life Cycle ◽

T Cell ◽

Mhc Class Ii ◽

Fungal Pathogen ◽

Antigen Processing ◽

Costimulatory Molecule ◽

Class Ii ◽

Normal Mixture ◽

Opportunistic Fungal Pathogen

ABSTRACT The life cycle of the opportunistic fungal pathogen Pneumocystis murina consists of a trophic stage and an ascus-like cystic stage. Infection with the cyst stage induces proinflammatory immune responses, while trophic forms suppress the cytokine response to multiple pathogen-associated molecular patterns (PAMPs), including β-glucan. A targeted gene expression assay was used to evaluate the dendritic cell response following stimulation with trophic forms alone, with a normal mixture of trophic forms and cysts, or with β-glucan. We demonstrate that stimulation with trophic forms downregulated the expression of multiple genes normally associated with the response to infection, including genes encoding transcription factors. Trophic forms also suppressed the expression of genes related to antigen processing and presentation, including the gene encoding the major histocompatibility complex (MHC) class II transactivator, CIITA. Stimulation of dendritic cells with trophic forms, but not a mixture of trophic forms and cysts, reduced the expression of MHC class II and the costimulatory molecule CD40 on the surface of the cells. These defects in the expression of MHC class II and costimulatory molecules corresponded with a reduced capacity for trophic form-loaded dendritic cells to stimulate CD4+ T cell proliferation and polarization. These data are consistent with the delayed innate and adaptive responses previously observed in immunocompetent mice inoculated with trophic forms compared to responses in mice inoculated with a mixture of trophic forms and cysts. We propose that trophic forms broadly inhibit the ability of dendritic cells to fulfill their role as antigen-presenting cells.

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Trogocytosis of peptide–MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1615973114 ◽

2017 ◽

Vol 114 (5) ◽

pp. 1111-1116 ◽

Cited By ~ 50

Author(s):

Kensuke Miyake ◽

Nozomu Shiozawa ◽

Toshihisa Nagao ◽

Soichiro Yoshikawa ◽

Yoshinori Yamanishi ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Differentiation ◽

Cell Surface ◽

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

Gm Csf ◽

Mhc Ii ◽

Th2 Cell ◽

Antigen Presenting

Th2 immunity plays important roles in both protective and allergic responses. Nevertheless, the nature of antigen-presenting cells responsible for Th2 cell differentiation remains ill-defined compared with the nature of the cells responsible for Th1 and Th17 cell differentiation. Basophils have attracted attention as a producer of Th2-inducing cytokine IL-4, whereas their MHC class II (MHC-II) expression and function as antigen-presenting cells are matters of considerable controversy. Here we revisited the MHC-II expression on basophils and explored its functional relevance in Th2 cell differentiation. Basophils generated in vitro from bone marrow cells in culture with IL-3 plus GM-CSF displayed MHC-II on the cell surface, whereas those generated in culture with IL-3 alone did not. Of note, these MHC-II–expressing basophils showed little or no transcription of the corresponding MHC-II gene. The GM-CSF addition to culture expanded dendritic cells (DCs) other than basophils. Coculture of basophils and DCs revealed that basophils acquired peptide–MHC-II complexes from DCs via cell contact-dependent trogocytosis. The acquired complexes, together with CD86, enabled basophils to stimulate peptide-specific T cells, leading to their proliferation and IL-4 production, indicating that basophils can function as antigen-presenting cells for Th2 cell differentiation. Transfer of MHC-II from DCs to basophils was also detected in draining lymph nodes of mice with atopic dermatitis-like skin inflammation. Thus, the present study defined the mechanism by which basophils display MHC-II on the cell surface and appears to reconcile some discrepancies observed in previous studies.

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Identification of Sulfavant A as the First Synthetic TREM2 Ligand Discloses a Homeostatic Response of Dendritic Cells After Receptor Engagement

10.21203/rs.3.rs-1211312/v1 ◽

2022 ◽

Author(s):

Carmela Gallo ◽

Emiliano Manzo ◽

Giusi Barra ◽

Laura Fioretto ◽

Marcello Ziaco ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Mhc Class Ii ◽

Molecular Mechanisms ◽

Vaccine Development ◽

Class Ii ◽

Receptor Activation ◽

T Cell Response ◽

Adjuvant Effect ◽

Adjuvant Activity

Abstract The immune response arises from a fine balance of cellular and molecular mechanisms that provide for surveillance, tolerance, and elimination of dangers as pathogens. Improving the quality of the immune response remains a major goal in immunotherapy and vaccine development. Sulfavant A (SULF A) is a sulfolipid that has shown promising adjuvant activity in a cancer vaccine model. Here we report that SULF A is the first synthetic small molecule binding to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2). The receptor engagement initiates an unconventional maturation of Dendritic cells (DCs) leading to upregulation of the Major Histocompatibility Complex class II (MHC Class II) and costimulatory molecules (CD83, CD86, DC54) without release of T helper type 1 (Th1) or 2 (Th2) cytokines. According to a TREM2 mechanism, this response is mediated by SYK-NFAT axis and is compromised by blockade and gene silencing of the receptor. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and induced interleukin-10 (IL-10) release after lipopolysaccharide (LPS) stimulation. These results well support the adjuvant effect of SULF A and offer novel insights into the role of TREM2 in the differentiation of an unprecedented DC phenotype (homeDCs) that contributes to the maintenance of immune homeostasis without compromising lymphocyte activation and immunogenic response. The biological function of SULF-A may be of interest in various physiological and pathological processes involving the immune system.

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Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells

The Journal of Cell Biology ◽

10.1083/jcb.200103071 ◽

2001 ◽

Vol 155 (1) ◽

pp. 53-64 ◽

Cited By ~ 196

Author(s):

Monique Kleijmeer ◽

Georg Ramm ◽

Danita Schuurhuis ◽

Janice Griffith ◽

Maria Rescigno ◽

...

Keyword(s):

Dendritic Cells ◽

Plasma Membrane ◽

Mhc Class Ii ◽

Class Ii ◽

Multivesicular Bodies ◽

Mhc Ii ◽

Immature Dendritic Cells ◽

Class Ii Mhc ◽

Accessory Molecule ◽

Class Ii Antigen

Immature dendritic cells (DCs) sample their environment for antigens and after stimulation present peptide associated with major histocompatibility complex class II (MHC II) to naive T cells. We have studied the intracellular trafficking of MHC II in cultured DCs. In immature cells, the majority of MHC II was stored intracellularly at the internal vesicles of multivesicular bodies (MVBs). In contrast, DM, an accessory molecule required for peptide loading, was located predominantly at the limiting membrane of MVBs. After stimulation, the internal vesicles carrying MHC II were transferred to the limiting membrane of the MVB, bringing MHC II and DM to the same membrane domain. Concomitantly, the MVBs transformed into long tubular organelles that extended into the periphery of the cells. Vesicles that were formed at the tips of these tubules nonselectively incorporated MHC II and DM and presumably mediated transport to the plasma membrane. We propose that in maturing DCs, the reorganization of MVBs is fundamental for the timing of MHC II antigen loading and transport to the plasma membrane.

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Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis

Blood ◽

10.1182/blood-2003-08-2729 ◽

2004 ◽

Vol 103 (6) ◽

pp. 2187-2195 ◽

Cited By ~ 123

Author(s):

Nicholas S. Wilson ◽

Dima El-Sukkari ◽

José A. Villadangos

Keyword(s):

Dendritic Cells ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Class Ii ◽

Lymphoid Organ ◽

Lymphoid Organs ◽

Mhc Ii ◽

Peptide Complexes ◽

Self Antigens

Abstract Dendritic cells (DCs) change their antigen-presenting properties during maturation. Immature DCs efficiently capture antigens, but are reported to be impaired in their processing and presenting capacity. Upon an encounter with an inflammatory stimulus, DCs undergo a maturation process that leads to efficient presentation of antigens captured at the time of activation, but precludes processing of antigens encountered at later time points. The mechanisms that underlie these developmental changes are controversial. Thus, it is unclear whether immature DCs can present self antigens, and which are the checkpoints that regulate antigen presentation in immature and mature DCs. We have characterized these mechanisms using DCs derived directly from lymphoid organs. Immature lymphoid organ DCs constitutively presented self peptides bound to major histocompatibility complex class II (MHCII) molecules, but these MHCII-peptide complexes were degraded quickly after their transient expression on the cell surface. During maturation, MHC II endocytosis was down-regulated, so that newly generated MHC II–peptide complexes accumulated on the plasma membrane. Simultaneously, MHC II synthesis was down-regulated, thus preventing the turnover of the MHC II–peptide complexes that accumulated early during maturation. Our results demonstrate that immature DCs constitutively present self antigens in the lymphoid organs and characterize the molecular basis of the capacity of DCs to provide “antigenic memory” in vivo.

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