Trends in Immunology
Chemokines: multiple levels of leukocyte migration control☆☆
Section snippets
Cellular production of chemokines
Chemokines are remarkably diverse, both in terms of individual proteins and their production by blood and tissue cells. Previously, chemokines were grouped into the functional subfamilies termed ‘inflammatory’ and ‘homeostatic’ chemokines (Table 1). Inflammatory chemokines control the recruitment of effector leukocytes in infection, inflammation, tissue injury and tumors. Many of the inflammatory chemokines have broad target-cell selectivity and act on cells of the innate, as well as the
Fine-tuning of chemokine function
Receptor binding and triggering are mediated by distinct epitopes in the NH2-terminal region of chemokines. Structure–activity studies, which revealed the importance of this region, were pioneered by the late Ian Clark-Lewis (see Acknowledgements), who generated a large number of chemically synthesized chemokine variants and hybrids [19]. This analysis led to the identification of the tri-peptide sequence Glu–Leu–Arg (ELR motif) in CXCL8 [interleukin-8 (IL-8)] and other CXCR1- or CXCR2-binding
Migration control during leukocyte development
The immune system is highly complex, both in terms of effector-cell variety and the multitude of leukocyte differentiation and maturation stages. Leukocyte development from precursors in the bone marrow and thymus is characterized by a flexibility in leukocyte migration properties, which enables coordinated relocation of individual precursors during their sequential steps of maturation. The need for precursor relocation is reflected by changes in the chemokine receptor profile and the selection
Control of effector or memory leukocyte traffic
Both inflammatory and homeostatic chemokines are involved in the traffic control of effector or memory cells, whereby inflammatory chemokines determine the cellular infiltrates at sites of pathogen entry and inflammation and homeostatic chemokines regulate the inflammation-unrelated, continuous traffic of memory cells through healthy peripheral tissues (Table 1). Of note, cells of the innate immune system are equipped with numerous receptors for inflammatory chemokines, which enable their
Perspectives
The large inventory of the molecular components of the chemokine system is largely known and many aspects of immunity that depend on chemokine-driven leukocyte traffic, relocation and co-localization can now be studied. The highly complex process of T-cell development, defined by the intricate migration properties of thymocytes that change along their route of maturation, can now be studied. Possibly, this will also contribute to a better understanding of B-cell development in follicular
Acknowledgements
This Review article is dedicated to the late Dr. Ian Clark-Lewis from the Biomedical Research Centre, University of British Columbia, Vancouver, Canada. We will always remember Ian as an expert collaborator as well as a welcome visitor and good friend of the Theodor-Kocher Institute. We are thankful to Marco Baggiolini for critical review of our manuscript. This work was supported in part by Swiss National Science Foundation grants 31–055996.98 to B.M. and M.W., 31–57399.99 to A.W. and grant
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Supplementary data associated with this paper can be found at doi: 10.1016/j.it.2003.12.005