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IMMUNOLOGY: ON DENDRITIC CELLS

The following points are made by S. Burns and A.J. Thrasher (Current Biology 2004 14:R965):

1) The control of the immune system by dendritic cells has become one of the most prominent areas of immunological research. These multitalented cells, originating from bone marrow precursors, reside in an immature state in most non-lymphoid tissues, continuously sampling their environment by endocytosis, macropinocytosis, and phagocytosis. In the presence of infection or inflammation, the actions of soluble mediators, such as interferons, and stimulation through members of the Toll-like receptor (TLR) and tumor necrosis factor receptor (TNF-R) families, initiate a complex maturation process that promotes the migration of dendritic cells to secondary lymphoid organs, where spatiotemporal regulation of the interaction with T cells provides the platform for induction of protective immunity [1].

2) Good evidence also exists for a constitutive traffic of dendritic cells in the absence of activating signals, which may be important for the control of peripheral tolerance [2]. In other words, these cells act as a sophisticated bridge between innate and adaptive immune systems during protection against infection, and at the same time maintain an immunological status quo.

3) The mechanisms controlling these highly regulated processes are determined by a synthesis of extrinsic signals and changes in the intrinsic behavior of the cell itself. For example, maturation of dendritic cells is accompanied by a reduction in the capacity to capture new antigen, changes in chemokine receptor expression that promote entry into lymphatic vessels and lymphatic organs, and enhanced presentation of antigen-derived peptides on class I and class II major histocompatibility complex (MHC) molecules to T cells at organized contact sites known as "immune synapses" [1,3]. At every step of the way, these functional changes are associated with dynamic and specialized alterations in the configuration of the actin cytoskeleton, and although these are critical for the correct functioning of the cell (and most likely can be harmful if disturbed), our understanding of their regulation and purpose is at best sketchy.

4) As with all cells, the dendritic cell actin cytoskeleton undergoes controlled assembly and disassembly of actin filaments at specific subcellular locations. Depending on the requirement and context, this presumably facilitates the processes of tissue localization, antigen uptake, migration, homing, and cell-cell interaction. The participation of the Rho GTPases Cdc42, Rac, and Rho in the regulation of long dendritic processes and of specialized actin-rich adhesion plaques called podosomes in immature dendritic cells has been demonstrated using microinjection techniques in vitro[4,5], and although not proven, these GTPases are likely to provide important switches for at least some of these activities. Both Rac and Cdc42 are also required for efficient macropinocytosis/endocytosis and the Wiskott-Aldrich Syndrome Protein (WASp), a downstream effector for Cdc42, is essential for processing of particulate antigen, formation of podosomes, and effective migration [4].

References (abridged):

1. Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y.J., Pulendran, B. and Palucka, K. (2000). Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767-811

2. Steinman, R.M., Hawiger, D., Liu, K., Bonifaz, L., Bonnyay, D., Mahnke, K., Iyoda, T., Ravetch, J., Dhodapkar, M. and Inaba, K. et al. (2003). Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann. N.Y. Acad. Sci. 987, 15-25

3. Lanzavecchia, A. and Sallusto, F. (2000). From synapses to immunological memory: the role of sustained T cell stimulation. Curr. Opin. Immunol. 12, 92-98

4. Burns, S., Thrasher, A.J., Blundell, M.P., Machesky, L. and Jones, G.E. (2001). Configuration of human dendritic cell cytoskeleton by Rho GTPases, the WAS protein, and differentiation. Blood 98, 1142-1149

5. Swetman, C.A., Leverrier, Y., Garg, R., Gan, C.H., Ridley, A.J., Katz, D.R. and Chain, B.M. (2002). Extension, retraction and contraction in the formation of a dendritic cell dendrite: distinct roles for Rho GTPases. Eur. J. Immunol. 32, 2074-2083

Current Biology http://www.current-biology.com

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Related Material:

IMMUNOLOGY: T-CELL SYNAPSES

Notes by ScienceWeek:

The so-called "adaptive immune system" of vertebrates, the system that responds in an adaptive manner to specific pathogen-derived or non-pathogenic foreign chemical entities, provides a protective system that distinguishes foreign proteins from the proteins of the organism itself. The foreign material (or part of the foreign material) that is recognized as such by the immune system is denoted by the term "antigen". Usually the antigen is a protein or protein-attached moiety (hapten) that has entered the bloodstream of the animal, e.g., the coat protein of an infecting virus, or the cell-surface protein of a malignant cell. Exposure to an antigen initiates an immune response that specifically recognizes the antigen and destroys it.

Adaptive immune responses are in general the responsibility of white blood cells (leukocytes), particularly the so-called B-and T-lymphocytes (B-cells and T-cells), and in addition large amoeba-like cells called "macrophages". The lymphocytes are named after the tissue that produces them: in mammals, B-cells mature in bone marrow, while T-cells mature in the thymus gland. There are an estimated 10^(12) immune system cells in the human body, enough to constitute a large organ if they were all assembled together. In general, the term "lymphocyte" refers to any cell that circulates in the "lymph", a blood-plasma-like fluid circulating separately but connected to the blood system.

The adaptive immune system has many mechanisms to destroy an antigen invader, with the responses generally categorized into two types, the "humoral response" and the "cell-mediated response".

The humoral response depends primarily on B-cells, aided by certain "helper T-cells" which provoke proliferation of B-cells, and involves the secretion of specific antibodies by B-cells, the antibodies consisting of proteins of the immunoglobulin class that bind to specific antigens.

The cell-mediated immune response is executed by both helper T-cells and a class of T-lymphocytes called cytotoxic T-cells ("killer T-cells"), which attack host cells that have been infected by a pathogen. In the cell-mediated immune response, T-cells may also begin a T-cell proliferation process as a result of contact with an "antigen-presenting cell" (see below), the proliferation involving cellular specialization (differentiation) and the production of a large number of specific-antigen-activated T-cells from a single progenitor cell (clonal expansion).

The basic function of the T-cell in recognizing a target antigen involves the use of T-cell surface receptors to recognize an antigen when it is presented on the surface of another cell, either an infected target cell or an immune system antigen-presenting cell. In the former case, various antigen fragments of the infecting intracellular pathogen are transported to the host-cell surface; in the latter case, immune system cells specialized to present antigens on their surfaces are involved, the antigens derived from engulfment (phagocytosis) and fragmentation of the pathogen. In both cases, the antigen is presented on the cell surface by a special protein called "major histocompatibility complex" (MHC), and in order for the antigen to be recognized by the T-cell, the antigen must be presented by one of the MHC group of proteins. It is apparently the combination of the antigen peptide fragment and MHC protein which is recognized by the T-cell receptor.

In general, then, T-cells have various roles in immune responses: there are types of T-cells involved in the humoral immune response and types of T-cells involved in the cell-mediated immune response. But in both cases, T-cell receptors interact with antigen-MHC complexes presented by an "antigen-presenting cell": in the case of the humoral immune response, the antigen-presenting cell is a host immune system cell which presents to the T-cells an antigen-MHC entity derived from the pathogen, and the T-cells (in this case, helper T-cells) are then involved in antibody production by B-cells; in the case of the cell-mediated immune response, the antigen-MHC-presenting cell is an infected host cell, the responding T-cells are helper T-cells and cytotoxic T-cells, with both helper T-cells and cytotoxic T-cells indirectly and directly involved, respectively, in the destruction of the infected host cell. Another generalization is that the humoral immune response is primarily directed against extracellular pathogens or pathogen derivatives, while the cell-mediated immune response is primarily directed against intracellular pathogens (or, in special cases, malignant host or foreign tissue cells).

There is some evidence that when T-cell proliferation occurs, a sustained engagement of T-cell receptors with antigen-presenting host-cell surface complexes is necessary, with the recognition by the T-cell of an antigen-MHC entity then involving an actual long-term (e.g., minutes or hours) juxtaposition of the T-cell and antigen-presenting cell. This juxtaposition, the details of which are not yet clearly understood, is called the "immunological synapse". The physical juxtaposition of the cells, an actual binding of their two surfaces at one or more points, is apparently mediated by so-called "adhesion molecules", which are active not only in relation to immunological synapses, but also in relation to other processes involving both intercellular adhesion and adhesion of cells to the extracellular macromolecular matrix. Recent evidence indicates the immunological synapse consists of a central cluster of T-cell receptors surrounded by a ring of adhesion molecules.

The following points are made by A. Grakoui et al (Science 1999 285:221):

1) The authors present an experimental study of immunological synapses, the study including real-time imaging and quantitative analysis of a model system consisting of planar lipid bilayers on glass supports mimicking the plasma membranes of antigen-presenting cells. The authors incorporated fluorescent-labelled MHC peptides and relevant adhesion molecules into the bilayers, and then added living T-cells to the system, the T-cells forming points of contact with ligands in the bilayer.

2) The authors report their results indicate that immunological synapse formation involves an active and dynamic mechanism that allows T-cells to distinguish potential antigenic ligands. Initially, T-cell receptor ligands are engaged in an outermost ring of the nascent synapse. Transport of these complexes into the central cluster is dependent on T-cell receptor-ligand interaction kinetics. Finally, formation of a stable central cluster at the heart of the synapse is apparently a determinative event for T-cell proliferation.

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