scholarly journals Selenoproteins Regulate Antigen Processing and Presentation in Antigen Presenting Cells (P24-024-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sarah Sumner ◽  
Bhuvana Katkere ◽  
Mckayla Nicol ◽  
Rachel Markley ◽  
Ashley Shay ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Antigen Presentation ◽  
Antigen Processing ◽  
Antigen Presenting Cells ◽  
Underlying Mechanism ◽  
Cell Receptor ◽  
Calcium Flux ◽  
Funding Sources ◽  
Antigen Presenting

Abstract Objectives Selenium (Se), which exerts its effects via selenoproteins, is an essential micronutrient that has been shown to be required for optimal functioning of the immune system. Although numerous studies have examined the effects of selenoproteins on various aspects of the immune response, few studies have investigated the effects of Se on antigen presentation. Moreover, these studies have provided conflicting results indicating the need for further research regarding the effect of Se on Antigen Presenting Cells (APCs). Our goal is to identify the role of selenoproteins in antigen presentation in professional APCs. Methods Mice deficient in selenoproteins in a cell specific manner were generated by knocking out the trspgene, which encodes for an essential tRNA for selenocysteine synthesis, utilizing the cre/lox system. The resulting mice are referred to asTrspDCand TrspBrepresenting selenoprotein deficiency specifically in dendritic cells (DCs) and B cells, respectively. Additional studies were done utilizing a diet model of Se deficiency to isolate Se-deficient DCs and B cells. Rate of endocytosis by specific receptors and expression of various surface molecule characteristics of APCs were determined by flow cytometry. Degradation of antigens by APCs in the presence or absence of selenoproteins was measured by western blot. Results In B cells, selenoprotein deficiency results in a decrease in the number of B220 + Splenocytes, B Cell Receptor (BCR) endocytosis, calcium flux following antigen stimulation, and BCR degradation following internalization. Similarly, selenoprotein deficiency in DCs results in decreased DEC-205 (a collectin-like receptor for multiple antigens) endocytosis; and a reduction in the expression of MHCII, CD80, and CD86. These results suggest a role for selenoproteins during the processing and presentation of peptides to T cells. Conclusions Loss of selenoproteins results in the decreased functionality of both B cells and DCs, which suggests that Se and selenoproteins may be involved in the regulation of antigen presentation. Further studies are needed to elucidate the underlying mechanism by which selenoproteins regulate antigen presentation. Such studies are likely to reveal novel targets for enhancing the immune response to vaccines and other specific antigens. Funding Sources NIH/NIAID to GK; NIH/GM to SS; NIH/NIDDK to KSP.

scholarly journals Abortive Proliferation of Rare T Cells Induced by Direct or Indirect Antigen Presentation by Rare B Cells In Vivo

1998 ◽  
Vol 187 (10) ◽  
pp. 1611-1621 ◽  
Author(s):  
Sarah E. Townsend ◽  
Christopher C. Goodnow
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presentation ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Antigen Presenting

Antigen-specific B cells are implicated as antigen-presenting cells in memory and tolerance responses because they capture antigens efficiently and localize to T cell zones after antigen capture. It has not been possible, however, to visualize the effect of specific B cells on specific CD4+ helper T cells under physiological conditions. We demonstrate here that rare T cells are activated in vivo by minute quantities of antigen captured by antigen-specific B cells. Antigen-activated B cells are helped under these conditions, whereas antigen-tolerant B cells are killed. The T cells proliferate and then disappear regardless of whether the B cells are activated or tolerant. We show genetically that T cell activation, proliferation, and disappearance can be mediated either by transfer of antigen from antigen-specific B cells to endogenous antigen-presenting cells or by direct B–T cell interactions. These results identify a novel antigen presentation route, and demonstrate that B cell presentation of antigen has profound effects on T cell fate that could not be predicted from in vitro studies.

scholarly journals Inhibition of CD1 Antigen Presentation by Human Cytomegalovirus

2008 ◽  
Vol 82 (9) ◽  
pp. 4308-4319 ◽  
Author(s):  
Martin J. Raftery ◽  
Manuel Hitzler ◽  
Florian Winau ◽  
Thomas Giese ◽  
Bodo Plachter ◽  
...  
Keyword(s):  
Immune Response ◽  
Antigen Presentation ◽  
Human Cytomegalovirus ◽  
Antigen Presenting Cells ◽  
Interleukin 10 ◽  
Antiviral Immune Response ◽  
Simplex Virus ◽  
Antigen Presenting ◽  
Group 1

ABSTRACT The betaherpesvirus human cytomegalovirus (HCMV) encodes several molecules that block antigen presentation by the major histocompatibility complex (MHC) proteins. Humans also possess one other family of antigen-presenting molecules, the CD1 family; however, the effect of HCMV on CD1 expression is unknown. The majority of CD1 molecules are classified on the basis of homology as group 1 CD1 and are present almost exclusively on professional antigen-presenting cells such as dendritic cells, which are a major target for HCMV infection and latency. We have determined that HCMV encodes multiple blocking strategies targeting group 1 CD1 molecules. CD1 transcription is strongly inhibited by the HCMV interleukin-10 homologue cmvIL-10. HCMV also blocks CD1 antigen presentation posttranscriptionally by the inhibition of CD1 localization to the cell surface. This function is not performed by a known HCMV MHC class I-blocking molecule and is substantially stronger than the blockage induced by herpes simplex virus type 1. Antigen presentation by CD1 is important for the development of the antiviral immune response and the generation of mature antigen-presenting cells. HCMV present in antigen-presenting cells thus blunts the immune response by the blockage of CD1 molecules.

Recipient Inflammation That Increases Alloimmunization Also Enhances Consumption of Transfused RBCs by Dendritic Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 23-23
Author(s):  
Jeanne E. Hendrickson ◽  
John D. Roback ◽  
Christopher D. Hillyer ◽  
James C. Zimring
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Antigen Presenting Cells ◽  
Poly I:C ◽  
Splenic Macrophages ◽  
Antigen Presenting

Background: Although much is known about the structure and immunogenicity of red blood cell (RBC) antigens, little is known about their processing and presentation by antigen presenting cells (APC). Red blood cells are a unique immunogen, in that they are given intravenously, without inflammation, and typically don’t enter peripheral tissues and lymphatics. Unlike pathogens, which cause an immune response in the majority of patients, only a small minority of chronically transfused patients develop alloantibodies to RBC antigens. In a murine model of RBC transfusion, we have previously reported that recipient inflammation, induced by Poly (I:C) (a double-stranded RNA that mimics viral inflammation), significantly enhances alloimmunization to RBC antigens. In this report, we explore the role of antigen presenting cells in the immune response to antigens on transfused RBCs, in an uninflammed state as well as in the presence of Poly (I:C). Methods: 3, 3-dihexadecyloxacarbocyanine perchlorate (DiO) was used as a fluorescent RBC label. Labeled RBCs were transfused into C57BL/6 recipient mice, in the absence or presence of inflammation with poly (I:C). 24 hours post-transfusion, APCs were analyzed in the spleen, liver, and lymph nodes. Macrophages (F4/80+) and dendritic cells (DC) (CD11c+) were gated on by flow cytometry, as were T cells (CD3+), B cells (CD19+) and RBCs (Terr 119+). RBC consumption was assessed by measuring DiO fluorescence in these cell populations. Results: In the absence of inflammation, the majority of RBCs are consumed by macrophages in the spleen, with 3 fold less consumption by liver macrophages and no consumption by lymph node macrophages. Both splenic and liver DCs consume 3 fold fewer RBCs than splenic macrophages. Recipient inflammation with Poly (I:C) alters this pattern, with a significant increase in consumption by both splenic and liver DCs and a decrease in consumption by splenic macrophages. As a negative control, no RBC consumption was seen after gating on non-phagocytic T cells or B cells. Likewise, measures of RBC consumption were not an artifact of RBC sticking to the APC surface, as staining for TER119 was negative. Discussion: Red blood cells are a unique immunogen, in that they circulate for many days, don’t enter lymphatics, and often don’t cause a detectable alloantibody response. These studies demonstrate that recipient inflammation with Poly (I:C), which we have previously reported enhances alloimmunization to transfused RBCs, significantly increases DC consumption of transfused RBCs. As DCs are typically considered to be more potent APCs than macrophages, and as we have previously shown that Poly (I:C) signficantly induces co-stimulatory molecule expression on DCs, these findings provide one potential mechanism by which inflammation enhances RBC alloimmunization. Ongoing studies are directly assessing the relative potency of these different APCs in their ability to activate CD4+ T cells specific for RBC antigens.

scholarly journals Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells

2015 ◽  
Vol 112 (33) ◽  
pp. 10449-10454 ◽  
Author(s):  
Kyung-Jin Cho ◽  
Even Walseng ◽  
Satoshi Ishido ◽  
Paul A. Roche
Keyword(s):  
B Cells ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Mhc Ii ◽  
Class Ii Mhc ◽  
Subsequent Degradation ◽  
Antigen Presenting

MHC class II (MHC-II)-dependent antigen presentation by antigen-presenting cells (APCs) is carefully controlled to achieve specificity of immune responses; the regulated assembly and degradation of antigenic peptide–MHC-II complexes (pMHC-II) is one aspect of such control. In this study, we have examined the role of ubiquitination in regulating pMHC-II biosynthesis, endocytosis, recycling, and turnover in APCs. By using APCs obtained from MHC-II ubiquitination mutant mice, we find that whereas ubiquitination does not affect pMHC-II formation in dendritic cells (DCs), it does promote the subsequent degradation of newly synthesized pMHC-II. Acute activation of DCs or B cells terminates expression of the MHC-II E3 ubiquitin ligase March-I and prevents pMHC-II ubiquitination. Most importantly, this change results in very efficient pMHC-II recycling from the surface of DCs and B cells, thereby preventing targeting of internalized pMHC-II to lysosomes for degradation. Biochemical and functional assays confirmed that pMHC-II turnover is suppressed in MHC-II ubiquitin mutant DCs or by acute activation of wild-type DCs. These studies demonstrate that acute APC activation blocks the ubiquitin-dependent turnover of pMHC-II by promoting efficient pMHC-II recycling and preventing lysosomal targeting of internalized pMHC-II, thereby enhancing pMHC-II stability for efficient antigen presentation to CD4 T cells.

scholarly journals Efficient T cell–B cell collaboration guides autoantibody epitope bias and onset of celiac disease

2019 ◽  
Vol 116 (30) ◽  
pp. 15134-15139 ◽  
Author(s):  
Rasmus Iversen ◽  
Bishnudeo Roy ◽  
Jorunn Stamnaes ◽  
Lene S. Høydahl ◽  
Kathrin Hnida ◽  
...  
Keyword(s):  
T Cells ◽  
Celiac Disease ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Disease Onset ◽  
Antigen Presenting Cells ◽  
Autoantibody Production ◽  
Antigen Presenting

B cells play important roles in autoimmune diseases through autoantibody production, cytokine secretion, or antigen presentation to T cells. In most cases, the contribution of B cells as antigen-presenting cells is not well understood. We have studied the autoantibody response against the enzyme transglutaminase 2 (TG2) in celiac disease patients by generating recombinant antibodies from single gut plasma cells reactive with discrete antigen domains and by undertaking proteomic analysis of anti-TG2 serum antibodies. The majority of the cells recognized epitopes in the N-terminal domain of TG2. Antibodies recognizing C-terminal epitopes interfered with TG2 cross-linking activity, and B cells specific for C-terminal epitopes were inefficient at taking up TG2-gluten complexes for presentation to gluten-specific T cells. The bias toward N-terminal epitopes hence reflects efficient T-B collaboration. Production of antibodies against N-terminal epitopes coincided with clinical onset of disease, suggesting that TG2-reactive B cells with certain epitope specificities could be the main antigen-presenting cells for pathogenic, gluten-specific T cells. The link between B cell epitopes, antigen presentation, and disease onset provides insight into the pathogenic mechanisms of a T cell-mediated autoimmune condition.

scholarly journals Human CD21low CD86pos B Cells Are Potent Antigen Presenting Cells, Which Are Expanded in Inflammatory Conditions

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3432-3432
Author(s):  
Alexander Shimabukuro-Vornhagen ◽  
María Alejandra García-Márquez ◽  
Rieke N. Fischer ◽  
Juliane Iltgen-Breburda ◽  
Anne Fiedler ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Research Funding ◽  
Cell Subset ◽  
Antigen Presenting Cells ◽  
Inflammatory Conditions ◽  
Advisory Boards ◽  
Antigen Presenting

Abstract Accumulating evidence from animal models demonstrates that antigen presentation by B cells plays a crucial role during the natural immune response as well as in several important diseases. While resting B cells are poor antigen-presenting cells they can acquire strong immunostimulatory properties after activation via receptors such as CD40. Studies in animal models suggest that ex vivo generated CD40-actived B cells could serve a promising platform of cellular cancer immunotherapy. However, our understanding of the function of antigen presentation by B cells in human remains limited. This is partly due to the lack of well-defined cell surface markers that can be used to identify distinct immunostimulatory B cell subsets. We hypothesized that antigen-presenting B cells in humans would be characterized by a similar phenotype than in vitro generated CD40-activated B cells. Using a transcriptomic approach combined with flow cytometric phenotypic screening, we were able to show that CD40-activated human B cells can be distinguished from resting B cells by high expression of costimulatory receptors and low expression of BCR-associated coreceptors such as CD21 and FcγRIIB. Here, we report that CD21low CD86pos B cells represent a distinct B lymphocyte subpopulation with potent immunostimulatory capacity. This antigen-presenting B-cell subset possesses phenotypic and functional features of strong antigen-presenting cells, i.e. they express high levels of costimulatory molecules and inflammatory adhesion molecules and low levels of ITIM-bearing inhibitory receptors. In vitro, purified human CD21low CD86pos B cells induced stronger T cell proliferation than the other three subsets, which are defined by the markers CD21 and CD86. Since Epstein Barr Virus (EBV) transforms human B cells with the help of the viral protein LMP1, which mimics CD40-mediated activation of B cells, we first studied patients with replicative EBV infection. We found that CD21low CD86pos B cells were expanded in severely immunosuppressed patients with EBV-reactivation. Analysis of CD21low CD86pos B lymphocytes in blood samples of healthy volunteers and patients with rheumatoid arthritis revealed that this subpopulation was increased in inflammatory conditions. One week following vaccination there was an increase in the frequency of this B-cell subset. Furthermore, compared to healthy controls CD21low CD86pos B cells were significantly elevated in the blood of patients with rheumatoid arthritis (RA). Interestingly, the CD21low CD86pos B-cell subset made up the majority of the B lymphocytes in synovial fluid of RA patients with inflammatory knee effusion. In summary, we demonstrate that CD21low CD86pos B cells are a novel antigen-presenting B-cell subset, which is expanded in inflammatory conditions. Our findings suggest that this subset might represent a promising therapeutic target for the treatment of inflammatory diseases, such as rheumatoid arthritis, were antigen presentation by B cells plays a pathogenetic role. Disclosures Hallek: Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

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