Trends in Immunology
Volume 25, Issue 2, February 2004, Pages 75-84
Journal home page for Trends in Immunology

Chemokines: multiple levels of leukocyte migration control☆

https://doi.org/10.1016/j.it.2003.12.005Get rights and content

Abstract

The surge in interest in chemokines is explained by the recognition that numerous aspects of immunity are intimately related to leukocyte traffic. Chemokines are leukocyte attractants but also contribute to immune processes that do not directly involve leukocyte migration. Recent progress is most evident in the areas of lymphocyte development, immune response initiation and immune pathology. Important observations have also been reported on chemokine–receptor interactions, signal transduction and cellular responses. New insights into the role of chemokines in leukocyte attraction and relocation will be discussed, with emphasis on the distinct levels of leukocyte migration control that ultimately determine the performance of our immune defense system.

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

References (81)

  • F. Annunziato

    Chemokines and lymphopoiesis in human thymus

    Trends Immunol.

    (2001)
  • T. Lapidot et al.

    Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells

    Exp. Hematol.

    (2002)
  • B. Moser

    CXCR5+T cells: follicular homing takes center stage in T-helper-cell responses

    Trends Immunol.

    (2002)
  • K.A. Papadakis

    CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn's disease

    Gastroenterology

    (2001)
  • E.J. Kunkel et al.

    Chemokines and the tissue-specific migration of lymphocytes

    Immunity

    (2002)
  • M.A. Wurbel

    Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor γδ+ gut intraepithelial lymphocytes

    Blood

    (2001)
  • E.J. Kunkel

    Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes

    Am. J. Pathol.

    (2002)
  • F. Katou

    Macrophage-derived chemokine (MDC/CCL22) and CCR4 are involved in the formation of T lymphocyte-dendritic cell clusters in human inflamed skin and secondary lymphoid tissue

    Am. J. Pathol.

    (2001)
  • C. Vestergaard

    A Th2 chemokine, TARC, produced by keratinocytes may recruit CLA+ CCR4+ lymphocytes into lesional atopic dermatitis skin

    J. Invest. Dermatol.

    (2000)
  • K. Ferenczi

    Increased CCR4 expression in cutaneous T cell lymphoma

    J. Invest. Dermatol.

    (2002)
  • C. Gerard et al.

    Chemokines and disease

    Nat. Immunol.

    (2001)
  • B. Moser et al.

    Lymphocyte traffic control by chemokines

    Nat. Immunol.

    (2001)
  • P.M. Murphy

    International union of pharmacology. XXII. Nomenclature for chemokine receptors

    Pharmacol. Rev.

    (2000)
  • P. Loetscher

    Chemokines and their receptors in lymphocyte traffic and HIV infection

    Adv. Immunol.

    (2000)
  • A.E. Proudfoot

    Chemokine receptors: multifaceted therapeutic targets

    Nat. Rev. Immunol.

    (2002)
  • M. Thelen

    Dancing to the tune of chemokines

    Nat. Immunol.

    (2001)
  • M. Baggiolini

    Interleukin-8 and related chemotactic cytokines – CXC and CC chemokines

    Adv. Immunol.

    (1994)
  • A. Richmond

    NF-κB, chemokine gene transcription and tumour growth

    Nat. Rev. Immunol.

    (2002)
  • K. Shortman et al.

    Mouse and human dendritic cell subtypes

    Nat. Rev. Immunol.

    (2002)
  • P. Loetscher et al.

    Homing chemokines in rheumatoid arthritis

    Arthritis Res.

    (2002)
  • J.E. Gretz

    Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex

    J. Exp. Med.

    (2000)
  • R.T. Palframan

    Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues

    J. Exp. Med.

    (2001)
  • M.J. Janatpour

    Tumor necrosis factor-dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocyte recruitment

    J. Exp. Med.

    (2001)
  • I. Clark-Lewis

    Structure-activity relationships of chemokines

    J. Leukoc. Biol.

    (1995)
  • J.P. Levesque

    Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide

    J. Clin. Invest.

    (2003)
  • I. Petit

    G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4

    Nat. Immunol.

    (2002)
  • A. Muller

    Involvement of chemokine receptors in breast cancer metastasis

    Nature

    (2001)
  • P. Loetscher et al.

    Agonistic and antagonistic activities of chemokines

    J. Leukoc. Biol.

    (2001)
  • T. Nagasawa

    A chemokine, SDF-1/PBSF, and its receptor, CXC chemokine receptor 4, as mediators of hematopoiesis

    Int. J. Hematol.

    (2000)
  • C.C. Bleul et al.

    Chemokines define distinct microenvironments in the developing thymus

    Eur. J. Immunol.

    (2000)
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    Supplementary data associated with this paper can be found at doi: 10.1016/j.it.2003.12.005

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