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Ana-Maria Lennon-Duménil

Publications and source records attributed to Ana-Maria Lennon-Duménil.

8 recordsLinked to original sources
PubMed2006

Antigen presentation by B lymphocytes: how receptor signaling directs membrane trafficking.

Antigen capture and presentation onto MHC class II molecules by B lymphocytes is mediated by their surface antigen receptor - the B-cell receptor (BCR). The BCR must therefore coordinate the transport of MHC class II- and antigen-containing vesicles for them to converge and ensure efficient processing. Recently, progress has been made in understanding which and how these vesicular transport events are molecularly linked to BCR signaling. In particular, recent studies have emphasized the key roles of membrane microdomains and the actin cytoskeleton in regulation of membrane trafficking upon BCR engagement.

Antigen Presentation↗
PubMed2006

NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells.

To initiate adaptative cytotoxic immune responses, proteolytic peptides derived from phagocytosed antigens are presented by dendritic cells (DCs) to CD8+ T lymphocytes through a process called antigen "crosspresentation." The partial degradation of antigens mediated by lysosomal proteases in an acidic environment must be tightly controlled to prevent destruction of potential peptides for T cell recognition. We now describe a specialization of the phagocytic pathway of DCs that allows a fine control of antigen processing. The NADPH oxidase NOX2 is recruited to the DC's early phagosomes and mediates the sustained production of low levels of reactive oxygen species, causing active and maintained alkalinization of the phagosomal lumen. DCs lacking NOX2 show enhanced phagosomal acidification and increased antigen degradation, resulting in impaired crosspresentation. Therefore, NOX2 plays a critical role in conferring DCs the ability to function as specialized phagocytes adapted to process antigens rather than kill pathogens.

Acid-Base Equilibrium↗
PubMed2005

Cathepsin L is essential for onset of autoimmune diabetes in NOD mice.

Lysosomal proteases generate peptides presented by class II MHC molecules to CD4+ T cells. To determine whether specific lysosomal proteases might influence the outcome of a CD4+ T cell-dependent autoimmune response, we generated mice that lack cathepsin L (Cat L) on the autoimmune diabetes-prone NOD inbred background. The absence of Cat L affords strong protection from disease at the stage of pancreatic infiltration. The numbers of I-A(g7)-restricted CD4+ T cells are diminished in Cat L-deficient mice, although a potentially diabetogenic T cell repertoire persists. Within the CD4+ T cell compartments of Cat L-deficient mice, there is an increased proportion of regulatory T cells compared with that in Cat L-sufficient littermates. We suggest that it is this displaced balance of regulatory versus aggressive CD4+ T cells that protects Cat L-deficient mice from autoimmune disease. Our results identify Cat L as an enzyme whose activity is essential for the development of type I diabetes in the NOD mouse.

Animals↗
PubMed2002

Invariant chain controls the activity of extracellular cathepsin L.

Secretion of proteases is critical for degradation of the extracellular matrix during an inflammatory response. Cathepsin (Cat) S and L are the major elastinolytic cysteine proteases in mouse macrophages. A 65 amino acid segment of the p41 splice variant (p41(65aa)) of major histocompatibility complex class II-associated invariant chain (Ii) binds to the active site of CatL and permits the maintenance of a pool of mature enzyme in endosomal compartments of macro-phages and dendritic cells (DCs). Here we show that interaction of p41(65aa) with mature CatL allows extracellular accumulation of the active enzyme. We detected mature CatL as a complex with p41(65aa) in culture supernatants from antigen-presenting cells (APCs). Extracellular accumulation of mature CatL is up-regulated by inflammatory stimuli as observed in interferon (IFN)-gamma-treated macrophages and lipopolysaccharide (LPS)-activated DCs. Despite the neutral pH of the extracellular milieu, released CatL associated with p41(65aa) is catalytically active as demonstrated by active site labeling and elastin degradation assays. We propose that p41(65aa) stabilizes CatL in the extracellular environment and induces a local increase in the concentration of matrix-degrading enzymes during inflammation. Through its interaction with CatL, Ii may therefore control the migratory response of APCs and/or the recruitment of effectors of the inflammatory response.

Alternative Splicing↗
PubMed2002

Analysis of protease activity in live antigen-presenting cells shows regulation of the phagosomal proteolytic contents during dendritic cell activation.

Here, we describe a new approach designed to monitor the proteolytic activity of maturing phagosomes in live antigen-presenting cells. We find that an ingested particle sequentially encounters distinct protease activities during phagosomal maturation. Incorporation of active proteases into the phagosome of the macrophage cell line J774 indicates that phagosome maturation involves progressive fusion with early and late endocytic compartments. In contrast, phagosome biogenesis in bone marrow-derived dendritic cells (DCs) and macrophages preferentially involves endocytic compartments enriched in cathepsin S. Kinetics of phagosomal maturation is faster in macrophages than in DCs. Furthermore, the delivery of active proteases to the phagosome is significantly reduced after the activation of DCs with lipopolysaccharide. This observation is in agreement with the notion that DCs prevent the premature destruction of antigenic determinants to optimize T cell activation. Phagosomal maturation is therefore a tightly regulated process that varies according to the type and differentiation stage of the phagocyte.

Animals↗
PubMed2002

Inflammatory stimuli recruit cathepsin activity to late endosomal compartments in human dendritic cells.

Proteolysis by endocytic cysteine proteases is a central element of the antigen-presentation machinery in dendritic cells (DC). It controls the generation of immunogenic peptides, guides the transit of both MHC class II and MHC-like molecules through the endocytic compartment and converts class II into a peptide-receptive state - features closely linked to DC maturation. Differential activity of endocytic proteases, in particular cathepsins, in subcellular compartments has been implicated as a key regulatory element in controlling this machinery in murine DC. We analyzed the expression and subcellular distribution of the major endocytic cysteine proteases (cathepsins S, B, L and H) along with their major endogenous inhibitor, Cystatin C, in resting and stimulated human DC. Although the majority of cathepsin activity was restricted to lysosomes in resting DC, cathepsins selectively accumulated in late endosomes after LPS-induced stimulation. Surprisingly, expression and distribution of Cystatin C was unaffected by DC maturation. Thus, late endosomes represent a specialized compartment where proteolytic activity is developmentally regulated in DC. This could facilitate the conversion of exogenous protein into MHC class II-peptide complexes.

Cathepsins↗
PubMed2002

A closer look at proteolysis and MHC-class-II-restricted antigen presentation.

Antigen presentation by MHC class II molecules relies on the action of endocytic proteases, which are differentially expressed in antigen-presenting cells and are regulated by different components of the immune system. Endocytic enzymes process and convert exogenous antigens into peptidic determinants capable of interaction with MHC class II molecules. Chemical and genetic tools have recently been developed to study the role of lysosomal proteases in antigen presentation.

Animals↗