A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1)

Abstract

SummaryChemotactic factors are postulated to direct emigration of lymphocytes from the blood stream into sites of inflammation. Members of a family ofchemotactic cytokines, termed chemokines, have been shown to attract lymphocytes but efficacy, i.e., the maximal percentage of attracted cells, has been low. We have identified a highly efficacious lymphocyte chemotactic activity in the supernatants of the murine bone marrow stroma cell line MS-5 which attracts 10-fold more lymphocytes in vitro than currently described lymphocyte chemoattractants. Purification of this chemotactic activity revealed identity to stromal cell-derived factor 1 (SDF-1). SDF-1 acts on lymphocytes and monocytes but not neutrophils in vitro and is both a highly efficacious and highly potent mononuclear cell attractant in vivo. In addition, SDF-1 induces intracellular actin polymerization in lymphocytes, a process that is thought to be a prerequisite for cell motility. Since SDF-1 is expressed constitutively in a broad range of tissues it may have a role in immune surveillance and in basal extravasation of lymphocytes and monocytes rather than in inflammation.L Ymphocytes function as the reservoir of immunological memory. In contrast to neutrophils and monocytes, lymphocytes may leave tissues through lymphatics, emigrate from the blood stream into lymphoid and non-lymphoid tissues, and recirculate multiple times during their life history (for review see reference 1). Chemoattractants are postulated to help direct lymphocyte traffic into sites of inflammation and into lymphoid and non-lymphoid tissues during recirculation (1, 2). The best lymphocyte chemoattractants identified to date are members of a family of small, 60 to 80 amino acid chemotactic cytokines termed chemokines. The chemokines can be divided into two subfamilies, the CXC-and the CC-chemokines. The members of each subfamily are more homologous to one another than to members of the other subfamily, and differ in the spacing of the first two cysteines. The two subfamilies differ in their chromosomal localization and cluster on chromosome 4 (CXC-chemokines) and chromosome 17 (CC-chemokines), respectively. While CXC-chemokines, e.g., interleukin 8 (IL-8), act mostly on neutrophils, members of the CC-chemokines, e.g., monocyte chemoattractant protein 1 (MCP-1) 1, regulated on activation normal T cell expressed 1Abbreviations used in this paper: MCP-1, monocyte chemoattractant protein 1; MIP-10t, macrophage inflammatory protein lce; RANTES, regulated on activation normal T cell expressed and secreted; SDF, stromal cellderived factor. and secreted (RANTES), and macrophage inflammatory protein lcl (MIP-lo0, have been shown to exert function on monocytes, eosinophils and lymphocytes (2, 3). However, the efficacy, i.e., the percent of attracted ceils, of lymphocyte chemoattractants described so far is low, whereas chemokines active on monocytes, neutrophils, and eosinophils are highly efficacious (2).The bone marrow not only produces precursor and immature lymphocytes, but also harbors m...

Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

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“…The chemokine receptor CXCR4 (map position 67 cM) is expressed on T lymphocytes and binds to the SDF-1␣/␤ ligand, and plays an important role in the activation of naïve CD45RA + T cells. 32 It has been proposed that antigen-presenting, SDF-1 secreting dendritic cells can acti- vate naïve CXCR4-positive naïve T cells upon migration to lymph nodes. 33 This region also contains the gene for interleukin 10 (IL-10; map position 70 cM), a cytokine produced by T cells (Th2) and macrophages, that blocks IFN-␥ synthesis by T cells, and cytokine synthesis by macrophages.…”

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“…While some authors were unable to detect expression of CXCR4 [6,7], others have described binding of SDF-1 § , SDF-1 § -induced Ca 2+ flux and migration [8][9][10]. We have detected a clear expression of CXCR4 on neutrophils from the synovial fluid of patients with different inflammatory joint diseases, whereas CXCR4 was hardly detectable in the peripheral blood of patients or normal blood donors, suggesting that CXCR4 on neutrophils could be functionally relevant in the setting of inflammation [11].…”

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“…30 SDF-1 is a chemokine that plays an important role in B-cell development, trafficking, and activation. [8][9][10][11] Several studies suggested that SDF-1 may have a crucial role in the development of autoimmune disease. Matin et al 31 demonstrated that the chemokine SDF-1 may be an essential chemoattractant in trafficking and migration of mature autoreactive B cells from bone marrow to the periphery or inflammatory sites in the development of autoimmune diabetes.…”

“…8 It is a chemoattractant for monocytes, naive and memory T lymphocytes, and B lymphocytes. [9][10][11] SDF-1 is also a costimulatory factor for CD4 þ T-lymphocyte activation. 12 In view of the presence of an important mononuclear cell infiltrate in SO, MCP-1 and SDF-1 are candidate chemokines for investigation.…”