Chemokines and Chemokine Receptors in Lymphocyte Traffic

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Since the discovery of IL-8, about 40 human chemokines and 16 chemokine receptors were characterized. Early on chemokines were considered as mediators of inflammation, but with time more and more chemokines were found that function mainly in the basal traffic of leukocytes, lymphocytes in particular. Inflammatory chemokines are induced by bacterial toxins and a number of cytokines, eg IL-1 a TNF, and can be produced locally in virtually all types of tissues as a consequence of inflammation or infection. The chemokines involved in the physiologic traffic of lymphocytes, by contrast, are produced constitutively in restricted regions. T lymphocytes express the widest variety of chemokine receptors and the expression is highly regulated. CXCR3, CCR1, CCR2 and CCR5, receptors for inflammatory chemokines, are upregulated by IL-2 in effector/memory T cells and decay rapidly when IL-2 is withdrawn or after stimulation with anti-CD3 and anti-CD28. Different stimulatory conditions modulate the expression of other receptors, eg CCR6, CCR7, or CXCR4, which have homeostatic rather than inflammatory functions. CCR7, for instance, is present at low levels in resting naive and memory T cells and is rapidly and transiently upregulated by stimulation with IL-2 and/or PHA. SLC and ELC, the ligands for CCR7, are constitutively expressed in secondary lymphoid tissues. The expression of different receptors on Th1 and Th2 cells provides a mechanism for their selective recruitment to inflammatory sites. For instance, the lymphocyte infiltrates in the pannus and synovial fluid of rheumatoid arthritis joints, which are rich in Th1 cells, are strongly positive for CCR5 and CXCR3.