Immune Complexes Inhibit Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells

Laborde, Evangelina; Vanzulli, Silvia I.; Beigier-Bompadre, Macarena; Isturiz, Martı́n A.; Ruggiero, Raúl A.; Fourcade, Mariano G.; Pellet, Antonio Catalán; Sozzani, Silvano; Vulcano, Marisa

doi:10.4049/jimmunol.179.1.673

Cited by 37 publications

(38 citation statements)

References 61 publications

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“…Aerobic glycolysis is an unlikely pathway of ATP production for nonproliferating cells (18). In addition, nonactivated DCs have been reported to rely on mitochondrial respiration (30,31); however, in light of our findings, these results might be specific for sparse cultures only. In LPS-activated murine DCs, glycolytic energy production is known to increase, as a specific adaptation mechanism for the increased intracellular nitrogen oxide levels that inhibits mitochondrial respiration, which scenario may not be applicable for MoDC development (19,32).…”

Section: Discussioncontrasting

confidence: 54%

Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid

Nasi

Fekete

Krishnamurthy

et al. 2013

The Journal of Immunology

147

118

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The demand for controlling T cell responses via dendritic cell (DC) vaccines initiated a quest for reliable and feasible DC modulatory strategies that would facilitate cytotoxicity against tumors or tolerance in autoimmunity. We studied endogenous mechanisms in developing monocyte-derived DCs (MoDCs) that can induce inflammatory or suppressor programs during differentiation, and we identified a powerful autocrine pathway that, in a cell concentration–dependent manner, strongly interferes with inflammatory DC differentiation. MoDCs developing at low cell culture density have superior ability to produce inflammatory cytokines, to induce Th1 polarization, and to migrate toward the lymphoid tissue chemokine CCL19. On the contrary, MoDCs originated from dense cultures produce IL-10 but no inflammatory cytokines upon activation. DCs from high-density cultures maintained more differentiation plasticity and can develop to osteoclasts. The cell concentration–dependent pathway was independent of peroxisome proliferator–activated receptor γ (PPARγ), a known endogenous regulator of MoDC differentiation. Instead, it acted through lactic acid, which accumulated in dense cultures and induced an early and long-lasting reprogramming of MoDC differentiation. Our results suggest that the lactic acid–mediated inhibitory pathway could be efficiently manipulated in developing MoDCs to influence the immunogenicity of DC vaccines.

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Section: Discussioncontrasting

confidence: 54%

Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid

Nasi

Fekete

Krishnamurthy

et al. 2013

The Journal of Immunology

147

118

View full text Add to dashboard Cite

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“…Functional defects in DCs, especially defects in DC maturation, have been shown to be involved in other common autoimmune diseases such as type 1 diabetes [41] (also lower IL-12 in diabetic children) [42], systemic lupus erythematosus [43], and arthritis [44]. Findings concerning the monogenic disease APECED and its causative gene AIRE have indicated that well-functioning peripheral and central tolerance are important in preventing autoimmunity in humans.…”

Section: Discussionmentioning

confidence: 99%

Critical immunological pathways are downregulated in APECED patient dendritic cells

et al. 2008

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE functions as a transcriptional regulator, and it has a central role in the development of immunological tolerance. AIRE regulates the expression of ectopic antigens in epithelial cells of the thymic medulla and has been shown to participate in the development of peripheral tolerance. However, the mechanism of action of AIRE has remained elusive. To further investigate the role of AIRE in host immune functions, we studied the properties and transcript profiles in in vitro © Springer-Verlag 2008 Correspondence to: Nora Pöntynen. Electronic supplementary material The online version of this article (doi:10.1007/s00109-008-0374-7) contains supplementary material, which is available to authorized users. Conflict of interest statement Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts monocyte-differentiated dendritic cells (moDCs) obtained from APECED patients and healthy controls. AIRE-deficient monocytes showed typical DC morphology and expressed DC marker proteins cluster of differentiation 86 and human leukocyte antigen class II. APECED patientderived moDCs were functionally impaired: the transcriptional response of cytokine genes to pathogens was drastically reduced. Interestingly, some changes were observable already at the immature DC stage. Pathway analyses of transcript profiles revealed that the expression of the components of the host cell signaling pathways involved in cell-cell signalling, innate immune responses, and cytokine activity were reduced in APECED moDCs. Our observations support a role for AIRE in peripheral tolerance and are the first ones to show that AIRE has a critical role in DC responses to microbial stimuli in humans.

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“…This isolation method is extensively employed [27,28], even though, it has been reported that the use of xenogeneic Abs could alter/activate Mos [29]. In this regard, FcγRIII (CD16 receptor) unlike FcγRI or FcγRII cross-linking, has not been associated to an impairment of DCs differentiation [30]. Interestingly, we found that the CD16 + Mo subset gave rise to a major CD1a − DC-SIGN low (CD16 + Mo-DC) population, while the CD16 − Mo subset gave rise to a main CD1a + DC-SIGN high (CD16 − Mo-DC) population (Fig.…”

Section: Cd16 + Mos Give Rise To Cd1a − Dc-sign Low Populationmentioning

confidence: 99%

Impaired dendritic cell differentiation of CD16‐positive monocytes in tuberculosis: Role of p38 MAPK

et al. 2013

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Tuberculosis (TB) is one of the world's most pernicious diseases mainly due to immune evasion strategies displayed by its causative agent Mycobacterium tuberculosis (Mtb). Blood monocytes (Mos) represent an important source of DCs during chronic infections; consequently, the alteration of their differentiation constitutes an escape mechanism leading to mycobacterial persistence. We evaluated whether the CD16 + /CD16 − Mo ratio could be associated with the impaired Mo differentiation into DCs found in TB patients. The phenotype and ability to stimulate Mtb-specific memory clones DCs from isolated Mo subsets were assessed. We found that CD16 − Mos differentiated into CD1a + DC-SIGN high cells achieving an efficient recall response, while CD16 + Mos differentiated into a CD1a − DC-SIGN low population characterized by a poor mycobacterial Ag-presenting capacity. The high and sustained phosphorylated p38 expression observed in CD16 + Mos was involved in the altered DC profile given that its blockage restored DC phenotype and its activation impaired CD16 − Mo differentiation. Furthermore, depletion of CD16 + Mos indeed improved the differentiation of Mos from TB patients toward CD1a + DC-SIGN high DCs. Therefore, Mos from TB patients are less prone to differentiate into DCs due to their increased proportion of CD16 + Mos, suggesting that during Mtb infection Mo subsets may have different fates after entering the lungs. Keywords: Dendritic cells r Monocyte differentiation r Tuberculosis See accompanying Commentary by Lugo-Villarino and NeyrollesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMonocytes (Mos) are large circulating leukocytes of the myeloid lineage that mediate essential functions of innate immunity including phagocytosis and cytokine production [1,2]. Mos are produced Correspondence: Dr. Luciana Balboa e-mail: luciana_balboa@hotmail.com in the bone marrow and released into the blood, and circulate in blood or reside in a spleen reservoir and, upon tissue infiltration they can differentiate into macrophages (M s) or DCs. Although human blood Mos are a highly heterogeneous population, two main subsets have been described: CD14 + CD16 − "classical" Mos are the major Mo population and CD14 + CD16 + Mos, the minor one (5-10% of total Mos). The latter subset has a more mature phenotype and an enhanced proinflammatory activity [3]. This heterogeneity has led to the hypothesis that Mos are committed to specific functions prior to tissue infiltration [4]. Also, C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 336Luciana Balboa et al. Eur. J. Immunol. 2013. 43: 335-347 an imbalance in the relative proportions of the subsets during acute inflammation [5] and several infectious diseases [6][7][8][9][10] including tuberculosis (TB) [11,12] has been described. TB, a disease that mainly affects the respiratory system, infects onethird of the world's population and kills 2 million people each year [13]. The success o...

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Immune Complexes Inhibit Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells

Cited by 37 publications

References 61 publications

Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid

Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid

Critical immunological pathways are downregulated in APECED patient dendritic cells

Impaired dendritic cell differentiation of CD16‐positive monocytes in tuberculosis: Role of p38 MAPK

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