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LIMLE, a new molecule over-expressed following activation, is involved in the stimulatory properties of dendritic cells.

ABSTRACT: Dendritic cells are sentinels of the immune system distributed throughout the body, that following danger signals will migrate to secondary lymphoid organs to induce effector T cell responses. We have identified, in a rodent model of graft rejection, a new molecule expressed by dendritic cells that we have named LIMLE (RGD1310371). To characterize this new molecule, we analyzed its regulation of expression and its function. We observed that LIMLE mRNAs were rapidly and strongly up regulated in dendritic cells following inflammatory stimulation. We demonstrated that LIMLE inhibition does not alter dendritic cell maturation or cytokine production following Toll-like-receptor stimulation. However, it reduces their ability to stimulate effector T cells in a mixed leukocyte reaction or T cell receptor transgenic system. Interestingly, we observed that LIMLE protein localized with actin at some areas under the plasma membrane. Moreover, LIMLE is highly expressed in testis, trachea, lung and ciliated cells and it has been shown that cilia formation bears similarities to formation of the immunological synapse which is required for the T cell activation by dendritic cells. Taken together, these data suggest a role for LIMLE in specialized structures of the cytoskeleton that are important for dynamic cellular events such as immune synapse formation. In the future, LIMLE may represent a new target to reduce the capacity of dendritic cells to stimulate T cells and to regulate an immune response.

SUBMITTER: Le Texier L

PROVIDER: S-EPMC3976354 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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LIMLE, a new molecule over-expressed following activation, is involved in the stimulatory properties of dendritic cells.

Le Texier Laëtitia L Durand Justine J Lavault Amélie A Hulin Philippe P Collin Olivier O Le Bras Yvan Y Cuturi Maria-Cristina MC Chiffoleau Elise E

PloS one 20140404 4

Dendritic cells are sentinels of the immune system distributed throughout the body, that following danger signals will migrate to secondary lymphoid organs to induce effector T cell responses. We have identified, in a rodent model of graft rejection, a new molecule expressed by dendritic cells that we have named LIMLE (RGD1310371). To characterize this new molecule, we analyzed its regulation of expression and its function. We observed that LIMLE mRNAs were rapidly and strongly up regulated in d ...[more]

PMID: 24705920

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Project description:Myeloid dendritic cells (DC) and macrophages play an important role in pathogen sensing and antimicrobial defense. Recently we demonstrated that infection of human DC with intracellular bacterium Listeria monocytogenes (L.monocytogenes) leads to the induction of the immunoinhibitory enzyme indoleamine 2,3-dioxygenase (Popov et al., J Clin Invest, 2006), while in the previous studies L.monocytogenes infection was associated with a rather stimulatory DC phenotype. To clarify this discrepancy we performed comparative microarray analysis of immature mo-DC (immDC), mature stimulatory mo-DC (matDC) and mature inhibitory DC either stimulated with prostaglandin E2 (PGE2-DC) or infected with L.monocytogenes (infDC). Studying infection of human myeloid DC with Listeria monocytogenes, we found out, that infected DC are modified by the pathogen to express multiple inhibitory molecules, including indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2, interleukin 10 and CD25, which acts on DC as IL-2 scavenger. All these inhibitory molecules, expressed on regulatory DC (DCreg), are strictly TNF-dependent and are in concert suppressing T-cell responses. Moreover, only DCreg can efficiently control the number of intracellular listeria, mostly by IDO-mediated mechanisms and by other factors, remaining to be identified. Analyzing publicly acessible data of transcriptional changes in DC and macrophages, infected by various pathogens and parasites (GEO, GSE360), we noticed that infection of these cells with Mycobacterium tuberculosis causes transcriptional response, comparable with the one caused by listeria in human DC. In fact, granuloma in tuberculosis and listeriosis in vivo are enriched for myeloid DC and macrophages characterized by regulatory phenotype. In summary, regulatory myeloid DC and macrophages may play a dual role during life-threatening granulomatous infections, such as tuberculosis: on one hand, regulatory myeloid cells promote pathogen containment by efficiently killing intracellular bacteria, on the other hand these cells inhibit granuloma-associated T cells and thereby might be involved in the retention of TNF-controlled granuloma integrity protecting the host from granuloma break-down and pathogen dissemination. Keywords: Cell type comparison, response to infection

Project description:Myeloid dendritic cells (DC) and macrophages play an important role in pathogen sensing and antimicrobial defense. Recently we demonstrated that infection of human DC with intracellular bacterium Listeria monocytogenes (L.monocytogenes) leads to the induction of the immunoinhibitory enzyme indoleamine 2,3-dioxygenase (Popov et al., J Clin Invest, 2006), while in the previous studies L.monocytogenes infection was associated with a rather stimulatory DC phenotype. To clarify this discrepancy we performed comparative microarray analysis of immature mo-DC (immDC), mature stimulatory mo-DC (matDC) and mature inhibitory DC either stimulated with prostaglandin E2 (PGE2-DC) or infected with L.monocytogenes (infDC). Studying infection of human myeloid DC with Listeria monocytogenes, we found out, that infected DC are modified by the pathogen to express multiple inhibitory molecules, including indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2, interleukin 10 and CD25, which acts on DC as IL-2 scavenger. All these inhibitory molecules, expressed on regulatory DC (DCreg), are strictly TNF-dependent and are in concert suppressing T-cell responses. Moreover, only DCreg can efficiently control the number of intracellular listeria, mostly by IDO-mediated mechanisms and by other factors, remaining to be identified. Analyzing publicly acessible data of transcriptional changes in DC and macrophages, infected by various pathogens and parasites (GEO, GSE360), we noticed that infection of these cells with Mycobacterium tuberculosis causes transcriptional response, comparable with the one caused by listeria in human DC. In fact, granuloma in tuberculosis and listeriosis in vivo are enriched for myeloid DC and macrophages characterized by regulatory phenotype. In summary, regulatory myeloid DC and macrophages may play a dual role during life-threatening granulomatous infections, such as tuberculosis: on one hand, regulatory myeloid cells promote pathogen containment by efficiently killing intracellular bacteria, on the other hand these cells inhibit granuloma-associated T cells and thereby might be involved in the retention of TNF-controlled granuloma integrity protecting the host from granuloma break-down and pathogen dissemination. Experiment Overall Design: Transcriptional profiles of immature mo-DC (immDC, n=3), mature stimulatory mo-DC (matDC, n=3) and mature inhibitory mo-DC either stimulated with prostaglandin E2 (PGE2-DC, n=3) or infected with L.monocytogenes (infDC, n=3) were compared on Affymetrix HG-U133A platform. All samples represent biological replicates and were processed separately throughout the experiment.

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LIMLE, a new molecule over-expressed following activation, is involved in the stimulatory properties of dendritic cells.

Publications

LIMLE, a new molecule over-expressed following activation, is involved in the stimulatory properties of dendritic cells.

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