Altered Antigen Presentation in Mice Lacking H2-O

Liljedahl, Monika; Winqvist, Ola; Surh, Charles D.; Wong, Phillip; Ngo, Karen; Teyton, Luc; Peterson, Per A.; Brunmark, Anders; Rudensky, Alexander Y.; Fung-Leung, Wai-Ping; Karlsson, Lars

doi:10.1016/s1074-7613(00)80475-6

Cited by 168 publications

(255 citation statements)

References 49 publications

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“…DO is widely thought to be an inhibitor of the peptide exchange activity of DM (18,20), and it has been proposed that the function of DO is to focus Ag processing in B cell onto BCR-internalized Ag (16,26). The colocalization results presented in this report suggest that DO may achieve this focusing by restricting DM-mediated class II peptide loading to intracellular compartments where Ag-BCR complexes persist for a prolonged period of time, allowing a greater time for the processing of BCR-internalized Ag and increasing the efficiency by which antigenic peptides are loaded onto MHC class II molecules.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Antigen Persistence Within Nonterminal Late Endocytic Compartments of Antigen-Specific B Lymphocytes

Gondré-Lewis

Moquin

Drake

2001

The Journal of Immunology

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Although Ag-specific B lymphocytes can process Ag and express peptide-class II complexes as little as 1 h after Ag exposure, it requires 3–5 days for the immune system to develop a population of Ag-specific effector CD4 T lymphocytes to interact with these complexes. Presently, it is unclear how B cells maintain the expression of cell surface antigenic peptide-class II complexes until effector CD4 T lymphocytes become available. Therefore, we investigated B cell receptor (BCR)-mediated Ag processing and presentation by normal B lymphocytes to determine whether these cells have a mechanism to prolong the cell surface expression of peptide-class II complexes derived from the processing of cognate Ag. Interestingly, after transit of early endocytic compartments, internalized Ag-BCR complexes are delivered to nonterminal late endosomes where they persist for a prolonged period of time. In contrast, Ags internalized via fluid phase endocytosis are rapidly delivered to terminal lysosomes and degraded. Moreover, persisting Ag-BCR complexes within nonterminal late endosomes exhibit a higher degree of colocalization with the class II chaperone HLA-DM/H2-M than with the HLA-DM/H2-M regulator HLA-DO/H2-O. Finally, B cells harboring persistent Ag-BCR complexes exhibit prolonged cell surface expression of antigenic peptide-class II complexes. These results demonstrate that B lymphocytes possess a mechanism for prolonging the intracellular persistence of Ag-BCR complexes within nonterminal late endosomes and suggest that this intracellular Ag persistence allows for the prolonged cell surface expression of peptide-class II complexes derived from the processing of specific Ag.

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Section: Discussionmentioning

confidence: 99%

Prolonged Antigen Persistence Within Nonterminal Late Endocytic Compartments of Antigen-Specific B Lymphocytes

Gondré-Lewis

Moquin

Drake

2001

The Journal of Immunology

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“…DO forms stable complexes with DM directly after its synthesis in the ER and is transported as such to the endosomal system (Liljedahl et al 1996). DO inhibits the peptideediting function of DM (Denzin et al 1997;van Ham et al 1997) particularly at mild acidic pH values (Kropshofer et al 1998;Liljedahl et al 1998;van Ham et al 2000). DO thus inhibits DM function early in the endocytic pathway but allows peptide editing by DM in more acidic, late endocytic compartments.…”

Section: Endosomal Mhc Class II Processingmentioning

confidence: 99%

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Broeke

Wubbolts

Stoorvogel

2013

Cold Spring Harbor Perspectives in Biology

139

102

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For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4 þ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane.

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“…Splenocytes were labeled with [ 35 S]methionine for 1 h and lysed in 1% Triton X-100 as described [67]. Briefly, H2-IA b was precipitated using the M5/114 antibody (kindly provided by L. Karlsson) and the immunoprecipitates were collected with protein G Sepharose, washed and resuspended in SDS-PAGE sample buffer containing 2% SDS without reduction.…”

Section: Metabolic Labeling and Immunoprecipitationmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

Self Cite

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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Altered Antigen Presentation in Mice Lacking H2-O

Cited by 168 publications

References 49 publications

Prolonged Antigen Persistence Within Nonterminal Late Endocytic Compartments of Antigen-Specific B Lymphocytes

Prolonged Antigen Persistence Within Nonterminal Late Endocytic Compartments of Antigen-Specific B Lymphocytes

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

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