Chemokine Receptors Beyond Migration of Leukocytes

Although the initial focus on this family of molecules concerned their effects on inflammatory leukocyte populations, it nonetheless became clear that che-mokines and their receptors functioned in arenas beyond this aspect of the immune system. One of the prominent early findings that catapulted chemo-kines into the limelight was the discovery that chemokine receptors acted as coreceptors for HIV-1 entry into susceptible cells (discussed in depth in Chapter 13). These included compelling experiments that identified the coreceptors, CCR5 and CXCR4, as well as studies that showed that chemokine ligands could block HIV-1 entry (11-17). Moreover, a polymorphism in CCR5 (delta-32) was discovered and shown to confer resistance to HIV infection. Although the lack of CCR5 in individuals harboring the CCR5 delta-32 mutation did not alter function from the chemokine biology point of view, it introduced investigators from multiple fields to chemokines biology. The significance of chemokine receptor usage by HIV became more striking when it was realized that the virus mutated toward utilization of CXCR4, correlating with the infection of T cells and subsequent development of AIDS. This set the stage for chemokines to become one of the most commonly investigated cytokine families. The next few years would establish an intense period of investigation and discovery in chemokine receptor biology, and the search for specific chemokine receptor blocking agents intensified.

Beyond roles of chemokine receptors in hematopoiesis and innate immunity, roles for chemokines in adaptive immunity emerged. Moreover, other non-leukocyte migration properties of chemokine receptors have been identified. These include roles in the biology of endothelial cells (Chapter 15), cancer (Chapter 16), smooth muscle (Chapter 11), fibroblasts (Chapter 14), stem cells (Chapter 8), and all cell types associated with nervous system tissues (Chapter 17). In many instances, broad functional overlap is evident as chemokines can direct the migration of these cells just as they do with leukocytes. In certain instances, the ability of chemokines to retain cell populations within a specific microenvironment is as important as their migration-promoting properties. However, it is also clear that migration and retention are not the sole end points.

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