Interplay of pathogens, cytokines and other stress signals in the regulation of dendritic cell function
Introduction
Dendritic cells (DCs) are highly specialized antigen-presenting cells with a unique ability to activate resting T lymphocytes owing to their efficiency to acquire and process antigens and their potential to express high levels of co-stimulatory molecules [1], [2], [3], [4]. Although well recognized for their ability to activate T cells, accumulating evidence shows that they also play an important role in the induction and maintenance of self-tolerance, a response directed to purge the peripheral T-cell repertoire of autoreactive T cells [5], [6], [7].
DCs do not constitute a unique cell population, but rather they comprise a large collection of subpopulations, located in both lymphoid and non-lymphoid tissues, that can be distinguished by the expression of specific cell surface markers and functional properties, perhaps reflecting a selective specialization in their response to infection [4], [8], [9], [10]. Two main DC subsets have been identified: conventional (“myeloid”) DCs and plasmacytoid DCs (pDCs). pDCs play a crucial role in antiviral immunity. They selectively express toll-like receptors (TLRs) 7 and 9, which enable them to sense single stranded RNA and DNA viruses, respectively, producing vast amounts of type I interferons (IFNs) [11], [12], [13]. In the present review we focus on conventional non-plasmacytoid DCs (hereafter called simply DCs).
DCs arise from progenitors present in the bone marrow through yet non-fully characterized intermediates [8], [9], [10], [14]. It is generally assumed that DC-precursors in the blood home to peripheral non-lymphoid tissues, particularly to sites of interface with the environment (skin and mucosa), where they reside as immature DCs. Immature DCs have a high capacity to sense, sample, and process incoming antigens, but a poor ability to stimulate naïve T cells. Upon maturation they become capable to trigger adaptive immunity by inducing the activation of naïve T cells and directing the differentiation of newly activated T lymphocytes into effector T cells [3], [4].
Section snippets
DCs capture antigens by macropinocytosis, receptor-mediated endocytosis and phagocytosis
Immature DCs have an extraordinary ability to sample the surrounding environment by macropinocytosis, receptor-mediated endocytosis and phagocytosis. They constitutively macropinocytose extracellular fluid, and also express a large variety of receptors mediating endocytosis and phagocytosis of antigens and pathogens [1], [15], [16], [17]. Macropinocytosis refers to the formation of large (1–3 μm) primary endocytic vesicles by the closure of lamellipodia generated at ruffling membrane domains.
Immature DCs express a variety of receptors to sense danger signals
Fig. 1 summarizes information about the families of receptors expressed by immature DCs which enable them to sense their surrounding environment looking for ongoing dangerous processes. As a component of the innate immune system, DCs can recognize a limited but highly conserved set of molecular structures produced by pathogens (pathogen-associated molecular patterns, or PAMPs), which are directly recognized through a number of germ line encoded receptors called pattern-recognition receptors
Modulation of DC function by innate immune cells
Several reports have recently highlighted the relevance of the reciprocal interactions established among DCs and other innate cells during the early stages of innate immune responses. These interactions can take place in secondary lymphoid organs and/or inflamed peripheral tissues, and appear to play an important role in the control of the immune response.
Modulation of DC function by other stress stimuli
Studies of the mechanisms involved in the regulation of DC activity are mostly restricted to the action of cytokines, chemokines and microbial products. However, other stress signals generated during the course of dangerous processes have also shown to stimulate the activation of DCs. Considering that the development of acidic microenvironments is a hallmark of inflammatory processes we have analyzed the influence of extracellular acidosis on the function of DCs. Our results indicated that DCs
Concluding remarks
Emerging concepts about innate immunity indicate that DCs play a crucial role in sensing environment signals and integrating this information to determine the profile of the adaptive immunity. A variety of signals including cytokines, chemokines, PAMPs, and other less characterized stress molecules have shown to be able to modulate the function of immature DCs and to determine distinct programs of DC differentiation and different forms of immunity. Further studies are needed to define how DCs
Acknowledgements
This work was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), University of Buenos Aires School of Medicine, and Agencia Nacional de Promoción Científica y Tecnológica, Argentina. We thank Dr. Analía Trevani for critical review of the manuscript.
Juan Sabatté obtained his MD degree from Buenos Aires University, School of Medicine. He is a PhD student with a fellowship from the National Council for Research and Technology (CONICET). The main focus of his research is to define the mechanisms through which the human immunodeficiency virus (HIV) modulates the function of dendritic cells.
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Cited by (0)
Juan Sabatté obtained his MD degree from Buenos Aires University, School of Medicine. He is a PhD student with a fellowship from the National Council for Research and Technology (CONICET). The main focus of his research is to define the mechanisms through which the human immunodeficiency virus (HIV) modulates the function of dendritic cells.
Julian Maggini obtained his MD degree from Buenos Aires University, School of Medicine and completed medical residency at the Austral University Hospital (Argentina). He is currently a PhD student with a fellowship from Repsol-YPF. His research project is focused on the ability of innate immune cells to modulate the function of dendritic cells.
Karen Nahmod obtained her MD degree from Buenos Aires University, School of Medicine. She is a PhD student with a fellowship from the National Council for Research and Technology (CONICET). The main focus of her research is to determine the influence of the renin-angiotensin-system (RAS) on the differentiation and function of dendritic cells.
María Marta Amaral has a degree in Biology from the Buenos Aires University, School of Exact Sciences and Natural Sciences, Argentina. She is a PhD student with a fellowship from the National Agency for the Promotion of Science and Technology (ANPCyT). Her research project is focused on the modulatory actions exerted by histamine on immune cells.
Diego Martínez has a degree in Biochemistry from the Buenos Aires University, School of Biochemistry. He is a PhD student with a fellowship from the Buenos Aires University. His research is focused on the mechanisms through which extracellular protons induce the activation of neutrophils and dendritic cells.
Gabriela Salamone obtained her PhD in Immunology from the Buenos Aires University, School of Exact Sciences and Natural Sciences, Argentina. She is a member of the scientist research career at the National Council for Research and Technology (CONICET). Her research Project is directed to characterize neuroendocrine mechanisms able to modulate the function of innate immune cells.
Ana Ceballos obtained her PhD in Virology from the Buenos Aires University, School of Exact Sciences and Natural Sciences, Argentina. She is a member of the scientist research career at the National Council for Research and Technology (CONICET). The main focus of her research is to characterize the mechanisms through which the human immunodeficiency virus (HIV) modulates the function of dendritic cells and other innate immune cells.
Mirta Giordano obtained her PhD in Immunology from the Buenos Aires University, School of Exact Sciences and Natural Sciences, Argentina. She is a member of the scientist research career at the National Council for Research and Technology (CONICET). Over the past 5 years, her research group has contributed broadly to the field of modulation of apoptosis of leukemic cells in chronic lymphocytic leukemia (CLL), the most common adult leukemia in Occident. At present, her research project is directed to understand the association between CLL and autoimmune hemolytic anemia (AHA).
Mónica Vermeulen obtained her PhD in Immunology from the Buenos Aires University, School of Exact Sciences and Natural Sciences, Argentina. She is a member of the scientist research career at the National Council for Research and Technology (CONICET). The main focus of her research is to understand the influence of extracellular acidosis on the function of innate immune cells.
Dr. Jorge Geffner is an Associate Professor of Immunology at the School of Medicine, Universidad de Buenos Aires, Argentina. He is a biochemist who obtained his PhD in Immunology from the Universidad de Buenos Aires, and is a member of the scientist research career at the National Council for Research and Technology (CONICET), Argentina. He has published over 60 original articles in leading Immunology journals. His research focuses on dendritic cells. Emerging concepts about innate immunity indicate that these cells play a crucial role in sensing environment signals and integrating this information to determine the profile of the adaptive immunity. Considering that the development of acidic microenvironments is a hallmark of inflammatory processes, Geffner and colleagues currently seek to characterize the influence of extracellular acidosis on the function of dendritic cells as well as the mechanisms through which innate immune cells recognize protons as a danger signal.