Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

https://www.cell.com/trends/immunology/pdf/S1471-4906(04)00295-9.pdf

The chemokine system in diverse forms of macrophage activation and polarization.

Recognition of microbial infection and initiation of host defense responses is controlled by multiple mechanisms. Toll-like receptors (TLRs) have recently emerged as a key component of the innate immune system that detect microbial infection and trigger antimicrobial host defense responses. TLRs activate multiple steps in the inflammatory reactions that help to eliminate the invading pathogens and coordinate systemic defenses. In addition, TLRs control multiple dendritic cell functions and activate signals that are critically involved in the initiation of adaptive immune responses. Recent studies have provided important clues about the mechanisms of TLR-mediated control of adaptive immunity orchestrated by dendritic cell populations in distinct anatomical locations.

Toll-like receptor control of the adaptive immune responses.

Chemokines: A New Classification System and Their Role in Immunity

Chemokines constitute a family of chemoattractant cytokines and are subdivided into four families on the basis of the number and spacing of the conserved cysteine residues in the N-terminus of the protein. Chemokines play a major role in selectively recruiting monocytes, neutrophils, and lymphocytes, as well as in inducing chemotaxis through the activation of G-protein-coupled receptors. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. Both CCL2 and its receptor CCR2 have been demonstrated to be induced and involved in various diseases. Migration of monocytes from the blood stream across the vascular endothelium is required for routine immunological surveillance of tissues, as well as in response to inflammation. This review will discuss these biological processes and the structure and function of CCL2.

Monocyte chemoattractant protein-1 (MCP-1): an overview.

Dendritic cells (DC) migrate into inflamed peripheral tissues where they capture antigens and, following maturation, to lymph nodes where they stimulate T cells. To gain insight into this process we compared chemokine receptor expression in immature and mature DC. Immature DC expressed CCR1, CCR2, CCR5 and CXCR1 and responded to their respective ligands, which are chemokines produced at inflammatory sites. Following stimulation with LPS or TNF-alpha maturing DC expressed high levels of CCR7 mRNA and acquired responsiveness to the CCR7 ligand EBI1 ligand chemokine (ELC), a chemokine produced in lymphoid organs. Maturation also resulted in up-regulation of CXCR4 and down-regulation of CXCR1 mRNA, while CCR1 and CCR5 mRNA were only marginally affected for up to 40 h. However, CCR1 and CCR5 were lost from the cell surface within 3 h, due to receptor down-regulation mediated by chemokines produced by maturing DC. A complete down-regulation of CCR1 and CCR5 mRNA was observed only after stimulation with CD40 ligand of DC induced to mature by LPS treatment. These different patterns of chemokine receptors are consistent with "inflammatory" and "primary response" phases of DC function.

Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation

Leukocyte traffic through secondary lymphoid tissues is finely tuned by chemokines. We have studied the functional properties of a human T cell subset marked by the expression of CXC chemokine receptor 5 (CXCR5). Memory but not naive T cells from tonsils are CXCR5+ and migrate in response to the B cell–attracting chemokine 1 (BCA-1), which is selectively expressed by reticular cells and blood vessels within B cell follicles. Tonsillar CXCR5+ T cells do not respond to other chemokines present in secondary lymphoid tissues, including secondary lymphoid tissue chemokine (SLC), EBV-induced molecule 1 ligand chemokine (ELC), and stromal cell–derived factor 1 (SDF-1). The involvement of tonsillar CXCR5+ T cells in humoral immune responses is suggested by their localization in the mantle and light zone germinal centers of B cell follicles and by the concomitant expression of activation and costimulatory markers, including CD69, HLA-DR, and inducible costimulator (ICOS). Peripheral blood CXCR5+ T cells also belong to the CD4+ memory T cell subset but, in contrast to tonsillar cells, are in a resting state and migrate weakly to chemokines. CXCR5+ T cells are very inefficient in the production of cytokines but potently induce antibody production during coculture with B cells. These properties portray CXCR5+ T cells as a distinct memory T cell subset with B cell helper function, designated here as follicular B helper T cells (TFH).

https://rupress.org/jem/article-pdf/192/11/1553/1128221/001362.pdf

Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function

Immunosurveillance by Hematopoietic Progenitor Cells Trafficking through Blood, Lymph, and Peripheral Tissues

Dendritic cell (DC) presentation of self antigen to thymocytes is essential to the establishment of central tolerance. We show here that circulating DCs were recruited to the thymic medulla through a three-step adhesion cascade involving P-selectin, interactions of the integrin VLA-4 with its ligand VCAM-1, and pertussis toxin–sensitive chemoattractant signaling. Ovalbuminspecific OT-II thymocytes were selectively deleted after intravenous injection of antigen-loaded exogenous DCs. We documented migration of endogenous DCs to the thymus in parabiotic mice and after painting mouse skin with fluorescein isothiocyanate. Antibody to VLA-4 blocked the accumulation of peripheral tissue–derived DCs in the thymus and also inhibited the deletion of OT-II thymocytes in mice expressing membrane-bound ovalbumin in cardiac myocytes. These findings identify a migratory route by which peripheral DCs may contribute to central tolerance. The random rearrangement of T cell receptor genes in the thymus continuously generates autoreactive T cells that must be removed from the lymphocyte pool or be rendered innocuous to maintain selftolerance. Most T cells that encounter their cognate major histocompatibility complex (MHC)–peptide complex before completion of thymic development are eliminated by clonal deletion, a key process leading to central tolerance 1 . The presence of an agonist peptide in the thymus can also result in the differentiation of CD4 + CD25 + regulatory T cells 2 that impose tolerance in the periphery by dampening the response of conventional lymphocytes 3 . Central tolerance is therefore believed to be restricted to those antigens that gain access to the thymic environment and can be effectively displayed on the surface of antigen-presenting cells; that is, proteins that are expressed locally or that circulate in the bloodstream. Although some tissue-specific proteins may be expressed in the thymus 4,5 , no active transport of self antigens from the periphery has been described so far. Dendritic cells (DCs) are very efficient antigen-presenting cells found in all peripheral organs and lymphoid tissues. In the periphery, they are strategically positioned to sample antigens from tissues and carry them to draining lymph nodes for processing and presentation to recirculating T cells 6 . When exposed to appropriate stimuli such as lipopolysaccharide, proinflammatory cytokines or other indicators of cellular distress, DCs undergo maturation, resulting in enhanced antigen presentation and increased expression of costimutalory molecules 6 . The maturing DCs gain access to lymph nodes through afferent lymphatic vessels and induce naive T cells to proliferate and to differentiate into effector cells. Immature DCs are also thought to carry antigen to lymph nodes and to interact with naive T cells, but

https://www.researchgate.net/profile/Roberto_Bonasio/publication/6837671_Clonal_deletion_of_thymocytes_by_circulating_dendritic_cells_homing_to_the_thymus/links/0c960525e8fc1e1f2c000000.pdf

Patrick Schaerli

Papers

Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation

Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function

Immunosurveillance by Hematopoietic Progenitor Cells Trafficking through Blood, Lymph, and Peripheral Tissues

Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus.

Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues