Tissue Distribution of the DEC-205 Protein That Is Detected by the Monoclonal Antibody NLDC-145: II. Expression in Situ in Lymphoid and Nonlymphoid Tissues

doi:10.1006/cimm.1995.1110

Cellular Immunology

Volume 163, Issue 1, June 1995, Pages 157-162

https://doi.org/10.1006/cimm.1995.1110 Get rights and content

Abstract

The rat monoclonal antibody NLDC-145, which has been utilized as a marker for mouse dendritic cells in numerous studies, binds an antigen that is more broadly distributed. This antigen is a unique 205-kDa integral membrane glycoprotein called DEC-205, which we have recently purified in quantities sufficient for basic biochemical studies, N-terminal sequencing, and immunization of rabbits. In cytofluorographic experiments, both the new polyclonal antibody and the original monoclonal detected DEC-205 on many classes of nondendritic murine leukocytes, particularly B cells. The quantities of DEC-205 on the surfaces of these cells were 10 to 50 times lower than those on epidermal and bone marrow dendritic cells. Here we utilize these reagents to reassess the tissue distribution of DEC-205 by immunohistochemical staining of frozen sections from a variety of organs, and by multiple-organ immunoblotting. Abundant expression of DEC-205 was confirmed histologically on thymic and intestinal epithelia and on dendritic cells in the T cell areas of peripheral lymphoid organs. In addition, DEC-205 was visualized in several other locations: B lymphocytes within B cell follicles, the stroma of the bone marrow, the epithelia of pulmonary airways, and the capillaries of the brain. Immunoblotting confirmed the presence of substantial levels of DEC-205 protein in lysates prepared from lymphoid tissues and from lung, marrow, and intestine. Thus, while DEC-205 is expressed at high levels by dendritic cells, it is also expressed by a number of other cell types in situ.

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The ectodomain of the influenza A virus (IAV) M2 protein (M2e) is highly conserved, and it represents a promising candidate for the development of an “universal vaccine”. However, the low immunogenicity associated to M2e in a natural infection or in response to seasonal vaccines has led to explore new approaches to enhance it. In recent years, it has become clear that targeting antigens to dendritic cells (DC) is an efficient way to enhance immune responses against pathogens. In this work, the M2e peptide was chemically cross-linked to a monoclonal antibody (mAb) specific for DEC-205 (α-DEC-205:M2e), present on DC. BALB/c mice were inoculated subcutaneously (s.c.) three times with the conjugate equivalent to 1 µg of M2e, in the presence of polyinosinic-polycytidylic acid (poly I:C) as adjuvant. As controls, other groups of mice were inoculated under the same conditions with M2e cross-linked to an isotype control mAb (isotype:M2e), 5 µg of free M2e peptide, ovalbumin (OVA) cross-linked to the α-DEC-205 mAb (α-DEC-205:OVA) or poly I:C alone. Immunization with α-DEC-205-M2e induced high levels of serum antibodies (Abs) compared to isotype:M2e or to free M2e peptide, and in all cases IgG1 was predominant over IgG2a Abs. Furthermore, immunization with the α-DEC-205:M2e conjugate did not prevent morbidity, but it induced up to 76% protection against a heterosubtypic IAV lethal challenge. Contrasting with the 20 to 40% protection induced by isotype:M2e or by free M2e peptide. The protection induced by α-DEC-205:M2e conjugate was dependent on non-neutralizing serum Abs and independent of effector CD4⁺ T cells. These results show that targeting M2e to DEC-205 is a very effective alternative to induce strong heterosubtypic protection against an IAV infection.
Characterization and expression of DEC205 in the cDC1 and cDC2 subsets of porcine dendritic cells from spleen, tonsil, and submaxillary and mesenteric lymph nodes
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Conventional dendritic cells (cDCs) are divided into the following different subtypes: cDC1, which promotes a Th1 response, and cDC2, which stimulates a Th2 and Th17 response. These cells have not been characterized in porcine lymphoid tissues. DEC205 is a receptor that increases antigen presentation and allows DCs to cross-present antigens. The objectives of this work were to characterize cDCs subsets in the tonsil, submaxillary and mesenteric lymph nodes and spleen lymphoid tissues and to determine their expression of DEC205 by flow cytometry. The cDC1 (MHCII^highCADM1^highCD172a^−/low) and cDC2 (MHCII^highCADM1^highCD172a⁺) phenotypes were confirmed by the expression of characteristic cDC1 and cDC2 transcripts (FLT3, XCR1 and FCER1α). Among all lymphoid tissues, the spleen had the highest frequency of total cDCs. The cDC1:cDC2 ratio showed that all lymph tissues had higher levels of cDC1 than levels of cDC2. DEC205⁺ cDCs were found in all analyzed tissues, albeit with different frequencies. Our research will facilitate the study on the function of these cells and the investigation of the strategies for DEC205 targeting and functional studies.
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Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events, including the observation that there is a profound loss of gastrointestinal (GI) CD4⁺ T cells during acute HIV-1 infection, highlight the importance of inducing HIV-specific immunity within the gut. Here we report on the generation of cellular and humoral immune responses in the intestines by a mucosally administered, dendritic cell (DC) targeted vaccine. Our results show that nasally delivered α-CD205-p24 vaccine in combination with polyICLC, induced polyfunctional immune responses within naso-pulmonary lymphoid sites that disseminated widely to systemic and mucosal (GI tract and the vaginal epithelium) sites. Qualitatively, while α-CD205-p24 prime-boost immunization generated CD4⁺ T-cell responses, heterologous prime-boost immunization with α-CD205-p24 and NYVAC gag-p24 generated high levels of HIV-specific CD4⁺ and CD8⁺ T cells within the GI tract. Finally, DC-targeting enhanced the amplitude and longevity of vaccine-induced immune responses in the GI tract. This is the first report of a nasally delivered, DC-targeted vaccine to generate HIV-specific immune responses in the GI tract and will potentially inform the design of preventative approaches against HIV-1 and other mucosal infections.
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Citation Excerpt :
Mahnke et al. showed that Ag complexed to anti-DEC-205 is presented 30–100 times more efficiently than anti-MR [57]. DEC-205 is expressed at high levels on DCs in lymphoid tissues, and antibodies toward DEC-205 have increased antigen uptake 400 times more than untargeted antigen [58,59]. Several models have demonstrated that PLG nanoparticles (NPs) encapsulating Ag displaying antibodies against the CLRs DEC-205 or DC immunoreceptor (DCIR) were taken up by DCs compared to non-targeted NPs both in vitro and in vivo [19,60].
The induction of donor-specific tolerance to transplanted cells and organs, while preserving immune function as a whole, remains a highly sought after and elusive strategy for overcoming transplant rejection. Tolerance necessitates modulating a diverse array of cell types that recognize and respond to alloantigens, including antigen presenting cells and T lymphocytes. Nanotherapeutic strategies that employ cellular and biomaterial engineering represent an emerging technology geared towards the goal of inducing transplant tolerance. Nanocarriers offer a platform for delivering antigens of interest to specific cell types in order to achieve tolerogenic antigen presentation. Furthermore, the technologies also provide an opportunity for local immunomodulation at the graft site. Nanocarriers delivering a combination of antigens and immunomodulating agents, such as rapamycin, provide a unique technology platform with the potential to enhance outcomes for the induction of transplant tolerance.
Imbalance between CD205 and CD80/CD86 in dendritic cells in patients with immune thrombocytopenia
2015, Thrombosis Research
Citation Excerpt :
Thus, it was speculated that CD205 may be involved in the pathogenesis of ITP. CD205 is one of the least understood members of the macrophage mannose receptor family of C-type lectin receptors [3,4], which can capture endogenous glycoproteins and contribute to immune tolerance. It is an important tolerance-associated receptor that is mainly expressed in DCs and upregulated during DC maturation [5,6].
CD205(DEC-205), a tolerance-associated receptor, is a member of the macrophage mannose receptor family of C-type lectin receptors. Antigen uptake via CD205 induces regulatory T cells, thereby regulating peripheral immune tolerance. However, the contribution of CD205 to autoimmune diseases has not been elucidated. Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by overdestruction of platelets. A previous study by the present authors found that CD205 expression in dendritic cells (DCs) was upregulated during induction of immune tolerance in patients with ITP.
CD205 expression in monocyte-derived DCs and spleens from patients with ITP was analysed prior to and after high-dose dexamethasone (HD-DXM) treatment. Expression of CD80, CD86 and HLA-DR was also analysed in order to identify and define the maturation status of the DCs more precisely.
In patients with ITP, CD205 expression was found to be significantly decreased in DCs, and rare or absent in the border region of the spleen. However, the expression of CD80 and CD86 was increased in both monocyte-derived DCs and spleens in patients with ITP compared with controls. HD-DXM treatment may upregulate CD205 expression and downregulate CD80/CD86 expression, then rebalance the expression of CD205 and CD80/CD86 in DCs in patients with ITP.
Imbalance between CD205 and CD80/CD86 may contribute to the development of ITP. Therapies that aim to restore the balance between CD205 and CD80/CD86 may help to re-establish tolerance in patients with ITP.
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Regular ArticleTissue Distribution of the DEC-205 Protein That Is Detected by the Monoclonal Antibody NLDC-145: II. Expression in Situ in Lymphoid and Nonlymphoid Tissues

Abstract

Regular Article
Tissue Distribution of the DEC-205 Protein That Is Detected by the Monoclonal Antibody NLDC-145: II. Expression in Situ in Lymphoid and Nonlymphoid Tissues