@Adhesion molecules and chemokines
Chemokines comprise a large family of structurally related chemotactic cytokines that are 8 -14 kDa in size and positively charged. More than 40 chemokines have been reported and they can be classified into either of the four families according to the arrangement of the N-terminal cysteine residues, i.e., CXC, CC, CX3C, and C chemokines. The CXC family has the first two cysteine separated by one non-conserved amino acid residue (X), whereas the CC family has two cysteines in juxtaposition. The CX3C family has the two cysteines separated by three intervening amino acids, while the C family has only one cysteine residue. These chemokines act on various types of leukocytes through heptahelical (7-transmembrane-spanning), G-protein-coupled receptors, playing a crucial role in the formation of hemopoietic as well as lymphoid tissues and the regulation of leukocyte traffic or positioning.

Concerning receptors for chemokines, at least 17 members have so far been identified. They are classified according to the structure of the ligands at present, and the current nomenclature uses CXC, CC, CX3C or C followed by R (receptor) and a number (e.g., CXCR1 - 5, CCR1 - 10, CX3CR1 and XCR1). Following this nomenclature, a similar naming system has recently been proposed with their ligands, i.e., chemokines, in which each chemokine is also given a code number (e.g., CXCL1 - 15, CCL1 - 27, CX3CL1, XCL1 - 2, where L represents ligand [see Zlotnik & Yoshie, 2000]). While this nomenclature may alleviate confusion in the chemokine research, where a single chemokine often has multiple names that are sometimes termed differently between the human and mouse, it is often argued that simple code numbers are difficult to remember and even boring (look at the CD nomenclature which is, just as its name indicates, completely dull!).

Another degree of confusion in the chemokine research is conferred by the redundancy and binding promiscuity between many chemokines and their receptors. A single chemokine often binds to several receptors, whereas a single receptor may be signaled by multiple chemokines (for instance, a CC chemokine, RANTES, binds to trigger CCR1, 3, 5, whereas CCR1 allows binding of RANTES, MIP-1a, MCP-3 and other chemokines). However, to our relief, this promiscuity does not usually cross CXC versus CC chemokine boundaries, except that DARC (Duffy antigen for chemokine receptor; also a receptor for malarial parasites Plasmodium vivax and Plasmodium knowlesi) allows binding of both CXC and CC chemokines.

Functionally, chemokines can be divided into two kinds; inflammatory and homeostatic. Inflammatory chemokines are induced to high levels of expression by inflammatory stimuli such as IL-1, TNFa and LPS, and play important roles in the development of immune/inflammatory responses by attracting inflammatory cells. Typical examples include IL-8, eotaxin, MCP-1, IP-10, MIP-1b and RANTES. In contrast, homeostatic chemokines are usually constitutively expressed by a certain cell type(s) in a restricted tissue(s) and critically involved in the homeostatic regulation of lymphocyte trafficking and functional compartmentalization of lymphoid organs. Examples in this group include SLC, ELC, BCA-1/BLC, SDF-1 and TECK. SLC is constitutively produced by lymph node HEV cells, and mice lacking SLC or its receptor CCR7 show a selective defect in migration of T cells. BCA-1/BLC is constitutively produced by follicular dendritic cells, and mice deficient in BCA-1/BLC or its receptor CXCR5 have severe defect in development of B cell follicles in the spleen and Peyers patches. CXCR5-deficient mice also lack inguinal lymph nodes. Expression of some of these homeostatic chemokines seem to be under the control of the LT (lymphotoxin)/TNF family members and their receptors, while some chemokines appear to induce a positive feedback loop on LT expression.

Chemokine receptor expression appears to depend on the activation or differentiation state of T cells, and hence chemokine receptors are now used as markers for T cell differentiation. For instance, CCR1 (receptor for MIP-1a, RANTES), CCR5 (receptor for MIP-1a, MIP-1b, RANTES) and CXCR3 (receptor for Mig, IP-10) are expressed preferentially on Th1 cells, whereas CCR3 (receptor for eotaxin, MCP-2, -3), CCR4 (receptor for TARC, MDC), CCR8 (receptor for I-309) are expressed on Th2 cells. This regulated expression of chemokine receptors apparently plays a role in polarization of immune responses. For instance, IFNg produced by Th1 cells can induce Mig and IP-10, which is antagonized by IL-4. Since Th1 cells express CXCR3, a receptor for Mig and IP-10, this would give more bias toward Th1 responses. IL-4 and IL-13 produced by Th2 cells can induce eotaxin and MDC, which is antagonized by IFNg. Since Th2 cells express receptors for eotaxin and/or MDC (CCR3, 4), this would bias immune responses toward Th2 responses. In addition, CD4+ T cells expressing CXCR5 (receptor for BCA-1/BLC) have recently been reported to represent a unique subset of Th cells that localize to B cell follicles and provide B cell help (follicular B helper T cells; TFH).

In vitro studies indicate that some proteoglycans protect chemokines from degradation, act as chemokine storage and help present chemokines to their specific receptors. Other non-proteoglycan-type molecules such as mac25/angiomodulin and fibronectin also appear to have this function. In vivo, however, it remains fully explored how chemokines are presented to chemokine-receptor expressing cells. It is also a matter of conjecture how lymphocyte movement is determined under the condition where multiple chemokines that can affect lymphocyte motility are simultaneously present in situ.

Suggested further reading
1. Immunological Reviews, vol. 177, 2000: "Chemokines" (This volume represents a most comprehensive review on chemokines)
2. Ward, S.G. et al.: "Chemokines and T lymphocytes: More than an attraction". Immunity 9:1-11, 1998
3. Murdoch, C. & Finn, A.: "Chemokine receptors and their role in inflammation and infectious diseases". Blood 95:3032-3043, 2000.

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