Trends in Immunology

Trends in Immunology

Volume 22, Issue 2, 1 February 2001, Pages 83-87
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RANTES: a versatile and controversial chemokine

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Abstract

The activity of the chemokine RANTES is not restricted merely to chemotaxis. It is a powerful leukocyte activator, a feature potentially relevant in a range of inflammatory disorders. RANTES has attracted attention because it can potently suppress and, in some circumstances, enhance HIV replication. These characteristics are critically dependent on its ability to self-aggregate and bind to glycosaminoglycans.

Section snippets

RANTES: a pro-inflammatory chemokine

RANTES is a small protein of 68 amino acids and belongs to the rapidly growing chemokine family (for a general review on chemokines, see 1). RANTES induces leukocyte migration by binding to specific receptors in the seven-transmembrane G-protein-coupled receptor (GCPR) family, namely CCR1, CCR3, CCR4 and CCR5 (Fig. 1). It mediates the trafficking and homing of classical lymphoid cells such as T cells and monocytes, but also acts on a range of other cells, including basophils, eosinophils,

Diverse effects of RANTES on HIV replication

In 1995, RANTES was shown to be the most potent member of a trio of CC chemokines released by CD8? T cells that were able to suppress the replication of non-syncitium-inducing (NSI) HIV-1 strains in vitro [the others were macrophage inflammatory protein 1 α (MIP-1α) and MIP-1β] 10. These observations were fundamental to the identification of the receptor for these chemokines, CCR5, as the major co-receptor for cell entry of primary NSI HIV-1 strains 11. The precise mechanism of HIV suppression

RANTES does not behave as a typical chemokine at high concentrations

If RANTES derivatives are to be used as HIV-suppressive agents, then the effects of RANTES at high concentrations are not merely a matter of academic interest, as high peak concentrations of RANTES (up to 1 mg ml?1) could easily be achieved during intravenous administration. Initial studies of the biology of high RANTES concentrations (in the micromolar range) have led to some surprising findings.

The diverse biological effects of RANTES

Our current understanding of the effects of RANTES on T cells is summarized in Fig. 3. The exact signaling pathways appear to be very complex and are not yet fully characterized, especially as the same kinases can be induced within both the GPCR and GPCR-independent signaling pathways 35 (e.g. ZAP-70 and p125FAK) 20., 29.. The ability of RANTES to induce the GPCR-independent pathway and activate leukocytes is a distinct and important feature of the biology of this unusual chemokine. However,

RANTES biology: future directions

To answer the questions posed above, it is essential to define the precise in vivo role of RANTES. An invaluable model system would be the generation of transgenic mice expressing a non-aggregating (E66S) form of RANTES in place of the wild-type molecule. Although much less is known about murine RANTES biology, it seems highly likely that human (h) and mouse (m) RANTES share similar properties. The two proteins have considerable homology in both sequence and structure (Fig. 4): they share 83%

Acknowledgments

We are very grateful to L. Czaplewski, G. Trave, A. Gallimore and R. Dunbar for their support and for constructive discussions.

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