Abstract: Chemokines are a group of small (∼8–14 kDa), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of seven-transmembrane, G protein–coupled receptors. About 40 chemokines have now been identified in humans. They mainly act on neutrophils, monocytes, lymphocytes, and eosinophils and play a pivotal role in host defense mechanisms. The study of chemokines has recently overlapped more with other fields of immunology. It has now become evident that chemokines play fundamental roles in the development, homeostasis, and function of the immune system. The rapid increase in the number of chemokines along with other complex issues described below have led to a situation where a newcomer attempting to understand this field faces a daunting task. In this review, our goal is to present a concise overview of the chemokine superfamily. The chemokines have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system (24Ma Q Jones D Borghesani P.R Segal R.A Nagasawa T Kishimoto T Bronson R.T Springer T.A Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice.Proc. Natl. Acad. Sci. USA. 1998; 95: 9448-9453Crossref PubMed Scopus (1381) Google Scholar) or endothelial cells, where they result in either angiogenic or angiostatic effects (37Strieter R.M Polverini P.J Kunkel S.L Arenberg D.A Burdick M.D Kasper J Dzuiba J Van Damme J Walz A Marriott D et al.The functional role of the ELR motif in CXC chemokine-mediated angiogenesis.J. Biol. Chem. 1995; 270: 27348-27357Crossref PubMed Scopus (992) Google Scholar). However, the scope of this review makes it difficult to provide a comprehensive view of such a complex and expanding field. For this reason, we will focus on several areas of chemokine biology of particular interest to immunologists. The development of EST (expressed sequence tag) databases and bioinformatics (computer-assisted sequence analysis) have allowed the rapid identification of novel genes. The chemokines have been particularly well suited for these techniques since they represent very abundant messages in those cells that express them. Since they are small proteins, the probability that their entire coding regions were represented as ESTs in databases was very high. As a result, the chemokines have been one of the first molecular families to experience the full impact of genomics and bioinformatics, to the point that it is very likely that most of them have now been discovered. This allows us to take a global perspective of the field for useful lessons that we may be able to apply to other molecular families in the future. Table 1 shows the known human chemokines. One problem the field faced following the rapid pace of new chemokine discovery is that several groups often reported the same molecule under different names. This has led to significant confusion, even among scientists actively working in the field. To address this issue, the classification system presented in Table 1 was presented at the last Keystone Chemokine Symposium. Chemokines have been divided into the two major subfamilies on the basis of the arrangement of the two N-terminal cysteine residues, CXC and CC, depending on whether the first two cysteine residues have an amino acid between them (CXC) or are adjacent (CC). The genes for these families are currently designated SCY (small secreted cytokine) with SCYa corresponding to the CC subfamily and SCYb to the CXC subfamily. Two other classes of chemokines have been described: lymphotactin (C or SCYc) and fractalkine (CX3C or SCYd). The former one lacks cysteines one and three of the typical chemokine structure (22Kelner G.S Kennedy J Bacon K.B Kleyensteuber S Largaespada D.A Jenkins N.A Copeland N.G Bazan J.F Moore K.W Schall T.J et al.Lymphotactin a cytokine that represents a new class of chemokine.Science. 1994; 266: 1395-1399Crossref PubMed Scopus (614) Google Scholar), while the latter one exhibits three amino acids between the first two cysteines and is also the only membrane-bound chemokine through a mucin-like stalk (3Bazan J.F Bacon K.B Hardiman G Wang W Soo K Rossi D Greaves D.R Zlotnik A Schall T.J A new class of membrane-bound chemokine with a CX3C motif.Nature. 1997; 385: 640-644Crossref PubMed Scopus (1636) Google Scholar). The proposed chemokine nomenclature is based on the chemokine receptor nomenclature currently in use, which uses CC, CXC, XC, or CX3C followed by R (for receptor) and then a number. Thus, we have CCR1–9, CXCR1–5, XCR1 (the lymphotactin receptor), and CX3CR1 (the fractalkine receptor). Basically, the new nomenclature replaces R with L (ligand instead of receptor) to designate the ligands and uses CC for the SCYa family, CXC for SCYb, XC for SCYc, and CX3C for SCYd. The numbering system is the one already in use to designate the genes encoding each chemokine. Thus, a given gene will have the same number as its protein ligand (for example, ScyA 27 is the gene encoding CCL27), a correlation that should further simplify matters. Besides eliminating ambiguities, the new nomenclature directly indicates the class to which each chemokine belongs.Table 1CXC, C and, CX3C Chemokine/Receptor FamiliesCXC Chemokine/Receptor FamilySystematic NameHuman ChromosomeHuman LigandMouse LigandChemokine Receptor(s)CXCL14q12-q13GROα/MGSA-αGRO/KC?CXCR2 > CXCR1CXCL24q12-q13GROβ/MGSA-βGRO/KC?CXCR2CXCL34q12-q13GROγ/MGSA-γGRO/KC?CXCR2CXCL44q12-q13PF4PF4UnknownCXCL54q12-q13ENA-78LIX?CXCR2CXCL64q12-q13GCP-2CKα-3CXCR1, CXCR2CXCL74q12-q13NAP-2UnknownCXCR2CXCL84q12-q13IL-8UnknownCXCR1, CXCR2CXCL94q21.21MigMigCXCR3CXCL104q21.21IP-10IP-10CXCR3CXCL114q21.21I-TACUnknownCXCR3CXCL1210q11.1SDF-1α/βSDF-1CXCR4CXCL134q21BLC/BCA-1BLC/BCA-1CXCR5CXCL14UnknownBRAK/bolekineBRAKUnknown(CXCL15)UnknownUnknownLungkineUnknownC Chemokine/Receptor FamilySystematic NameHuman ChromosomeHuman LigandMouse LigandChemokine Receptor(s)XCL11q23Lymphotactin/SCM-1α/ATACLymphotactinXCR1XCL21q23SCM-1βUnknownXCR1CX3C Chemokine/Receptor FamilySystematic NameHuman ChromosomeHuman LigandMouse LigandChemokine Receptor(s)CX3CL116q13FractalkineNeurotactinCX3CR1CC Chemokine/Receptor FamilySystematic NameHuman ChromosomeHuman LigandMouse LigandChemokine Receptor(s)CCL117q11.2I-309TCA-3, P500CCR8CCL217q11.2MCP-1/MCAFJE?CCR2CCL317q11.2MIP-1α/LD78αMIP-1αCCR1, CCR5CCL417q11.2MIP-1βMIP-1βCCR5CCL517q11.2RANTESRANTESCCR1, CCR3, CCR5(CCL6)UnknownC10, MRP-1UnknownCCL717q11.2MCP-3MARC?CCR1, CCR2, CCR3CCL817q11.2MCP-2MCP-2?CCR3(CCL9/10)UnknownMRP-2, CCF18 MIP-1γUnknownCCL1117q11.2EotaxinEotaxinCCR3(CCL12)UnknownMCP-5CCR2CCL1317q11.2MCP-4UnknownCCR2, CCR3CCL1417q11.2HCC-1UnknownCCR1CCL1517q11.2HCC-2/Lkn-1/MIP-1δUnknownCCR1, CCR3CCL1617q11.2HCC-4/LECLCC-1CCR1CCL1716q13TARCTARCCCR4CCL1817q11.2DC-CK1/PARC AMAC-1UnknownUnknownCCL199p13MIP-3β/ELC/exodus-3MIP-3β/ELC/exodus-3CCR7CCL202q33-q37MIP-3α/LARC/exodus-1MIP-3α/LARC/exodus-1CCR6CCL219p136Ckine/SLC/exodus-26Ckine/SLC/exodus-2/TCA-4CCR7CCL2216q13MDC/STCP-1ABCD-1CCR4CCL2317q11.2MPIF-1UnknownCCR1CCL247q11.23MPIF-2/Eotaxin-2UnknownCCR3CCL2519p13.2TECKTECKCCR9CCL267q11.23Eotaxin-3UnknownCCR3CCL279p13CTACK/ILCALP/CTACK/ILC ESkineCCR10*We recently identified the receptor for CCL27, which has been named CCR10 (Homey et al. 2000).While we have tried to include most of the names with which a particular chemokine has been described, we may have missed some; for this we apologize in advance. We have also tried to list the main receptors for each chemokine, although some may bind other receptors but may not be their primary ligands. A question mark indicates that the listed mouse homolog may not correspond to the listed human ligand (see text). A systematic name in parenthesis indicates that the human homolog has not yet been identified.This provisional nomenclature proposal has been submitted to the International Union of Immunological Societies (IUIS) Subcommittee on Chemokine Nomenclature (chairman, R. Thorpe) for consideration as an internationally approved nomenclature.* We recently identified the receptor for CCL27, which has been named CCR10 (16Homey B Wang W Soto H Buchanan M Wiesenborn A Catron D Müller A McClanahan T Orozco R et al.The orphan chemokine receptor GPR-2 (CCR10) binds the skin-associated chemokine CCL27 (CTACK/ALP/ILC).J. Immunol. 2000; in pressGoogle Scholar). Open table in a new tab While we have tried to include most of the names with which a particular chemokine has been described, we may have missed some; for this we apologize in advance. We have also tried to list the main receptors for each chemokine, although some may bind other receptors but may not be their primary ligands. A question mark indicates that the listed mouse homolog may not correspond to the listed human ligand (see text). A systematic name in parenthesis indicates that the human homolog has not yet been identified. This provisional nomenclature proposal has been submitted to the International Union of Immunological Societies (IUIS) Subcommittee on Chemokine Nomenclature (chairman, R. Thorpe) for consideration as an internationally approved nomenclature. For many immunologists, it is important to know the mouse chemokines. The new nomenclature system, however, is currently focused on the human chemokines as “standard.” The chemokines described in other species can be grouped into four categories. (1) Chemokines that unambiguously (based on a high degree of sequence homology, and chromosomal location to syntenic regions between species) correspond to a given human ligand; examples include CCL5/RANTES, CCL17/TARC, CCL25/TECK, etc. (2) Chemokines related to a human homolog but whose exact homolog is not certain (indicated by a question mark in Table 1). Examples of this category include the monocyte chemotactic proteins CCL2/MCP-1, CCL7/MCP-2, CCL8/MCP-3, and CCL13/MCP-4, etc., of which there are currently four described in human and four in mouse (one of the latter present only in GenBank). Currently, because of their close sequence similarity, it is not possible to unambiguously determine which mouse ligand corresponds to which human ligand. Another example is CCL15/HCC2/leukotactin/MIP1δ, which could represent the human counterpart of either mouse C10 or mouse CCF18/mMRP2/MIP1γ. (3) Those chemokines for which no human counterpart has been described yet (e.g., CXCL15/lungkine [32Rossi D.L Hurst S.D Xu Y Wang W Menon S Coffman R.L Zlotnik A Lungkine, a novel CXC chemokine, specifically expressed by lung bronchoepithelial cells.J. Immunol. 1999; 162: 5490-5497PubMed Google Scholar]). Yet another category includes (4) human chemokines for which no mouse chemokine has been described (e.g., CXCL8/IL-8, CCL18/DC-CK-1/PARC). Thus, another advantage of looking at a molecular family globally is that we get closer to answering the question of how applicable are findings in mouse models to humans? The answer is that, to date, most chemokines have a corresponding human ligand, but not all. This is a situation that will no doubt apply to many other molecular families. However, the differences between the mouse and human chemokines not only reflect evolutionary patterns within this gene superfamily but also offer clues to understanding their biological functions. Most, if not all, chemokines probably arose from gene duplication from a single ancestral gene. Many chemokines are clustered in certain chromosomal locations (Table 1). Two main clusters have been recognized. Many human CXC chemokines that mainly act on neutrophils are clustered at chromosome 4q12–13, while many CC chemokines that mainly act on monocytes are located in another cluster at 17q11.2. However, the genes of the more recently discovered CC and CXC chemokines, which act mainly on lymphocytes, tend to be located elsewhere in new chromosomal locations away from the major clusters (Table 1). Interestingly, several chromosome 4 CXC chemokines that turned out to be highly specific for T lymphocytes (i.e., CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC) are also located in a minicluster separate from the major CXC cluster located in chromosome 4q12-q13. This diversification likely reflects functional specialization that has developed during the evolution of this superfamily and suggests that those chemokines located in different chromosomal locations from the major clusters are probably older in evolutionary terms and have remained more conserved between species because of their highly specific functions. They are also less likely to share receptors or overlap functions with other chemokines. In contrast, the major cluster chemokines (4q12–13 and 17q11.2) are likely to have been generated more recently in evolutionary terms. The fact that the genes encoding these chemokines were allowed by evolution to duplicate rapidly and form a cluster suggests that their functions remained to a certain extent related. This would explain why they share receptors extensively, do not exactly correspond genetically and functionally between mice and humans, and tend to act on the same leukocytes, neutrophils and monocytes. The multiplication of these “cluster” chemokines probably stems more from the quantitative need to produce a chemoattractant for either neutrophils or monocytes during inflammatory responses. Interestingly, some of these chemokines can exhibit relatively high specificity depending on the producing cell type (i.e., each cell type may produce its own version of chemoattractants for either neutrophils or monocytes). This production pattern probably reflects the different anatomical sites where each producing cell is located. Therefore, the functional specificities may be less important for this type of chemokine; their main function is likely to be the attraction of neutrophils or monocytes, while their specificity may be a secondary issue. In a sense they may be redundant, but they are nevertheless needed for the overall robust recruitment of these types of leukocytes. Therefore, one key concept in order to understand the physiology of the chemokine superfamily is to view these chemokine clusters as single entities based on their overall function. If we view the chemokine superfamily as a group of noncluster chemokines plus the two main clusters, we can conclude that there is little redundancy and good correlation between the functions of the human chemokines and those of other mammalian species. Besides accounting for a fresh perspective of the chemokine superfamily, this model has important implications for other gene families. The chemokine superfamily represents an example of the forces that shape evolution at the molecular level, which are a reflection of the function(s) of the genes involved. The biologic effects of the chemokines are mediated by seven-transmembrane-domain receptors that represent a subset of the G protein–coupled receptor (GPCR) superfamily. Most of them also exist in clusters that are located on chromosomes 2 and 3. At present, 16 receptors have been identified. Table 1 summarizes the correspondence between human chemokine ligands and human chemokine receptors. This table also shows redundancy and binding promiscuity between many ligands and receptors. This promiscuity is real because it involves high-affinity interactions. Thus, a single chemokine may bind to several receptors, whereas a single chemokine receptor may transduce signals for several chemokines. This is one of the most intriguing features of the chemokine superfamily and may reflect their ability to regulate many different leukocyte subpopulations, especially in complex microenvironments such as acute or chronic inflammatory responses. However, as we explained above, this is more common among the “cluster” chemokines than among those located in isolated chromosomal locations. Nevertheless, as we will see below, functional redundancy is not likely to be the rule in the chemokine superfamily. Rather, chemokines, especially the most recently discovered members of the superfamily, can exhibit high tissue and receptor specificity. Other chemokines play a pivotal role in homeostasis as well as in inflammatory responses that cannot be replaced with other chemokines. We will use as examples several areas of interest to immunologists, including lymphoid development, dendritic cells and the initiation of immune responses, and the Th1 and Th2 paradigm. We will describe a model of chemokine function that should clarify the function of chemokines in these areas and the implications of this model for the role of chemokines in the immune system. One of the most interesting recent developments in chemokine biology has been the association between chemokines and dendritic cells. Dendritic cells produce several chemokines, some of them in a highly specific manner. These include, for example, CCL17/TARC (17Imai T Yoshida T Baba M Nishimura M Kakizaki M Yoshie O Molecular cloning of a novel T cell-directed CC chemokine expressed in thymus by signal sequence trap using Epstein-Barr virus vector.J. Biol. Chem. 1996; 271: 21514-21521Crossref PubMed Scopus (272) Google Scholar, 35Sallusto F Palermo B Lenig D Miettinen M Matikainen S Julkunen I Forster R Burgstahler R Lipp M Lanzavecchia A Distinct patterns and kinetics of chemokine production regulate dendritic cell function.Eur. J. Immunol. 1999; 29 (a): 1617-1625Crossref PubMed Scopus (555) Google Scholar), CCL18/DC-CK-1/PARC (1Adema G.J Hartgers F Verstraten R de Vries E Marland G Menon S Foster J Xu Y Nooyen P McClanahan T et al.A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells.Nature. 1997; 387: 713-717Crossref PubMed Scopus (445) Google Scholar, 15Hieshima K Imai T Baba M Shoudai K Ishizuka K Nakagawa T Tsuruta J Takeya M Sakaki Y Takatsuki K et al.A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1 alpha/LD78 alpha and chemotactic for T lymphocytes, but not for monocytes.J. Immunol. 1997; 159: 1140-1149PubMed Google Scholar, 35Sallusto F Palermo B Lenig D Miettinen M Matikainen S Julkunen I Forster R Burgstahler R Lipp M Lanzavecchia A Distinct patterns and kinetics of chemokine production regulate dendritic cell function.Eur. J. Immunol. 1999; 29 (a): 1617-1625Crossref PubMed Scopus (555) Google Scholar), CCL25/TECK (40Vicari A.P Figueroa D.J Hedrick J.A Foster J.S Singh K.P Menon S Copeland N.G Gilbert D.J Jenkins N.A Bacon K.B Zlotnik A TECK a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development.Immunity. 1997; 7: 291-301Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar), CCL22/MDC (11Godiska R Chantry D Raport C.J Sozzani S Allavena P Leviten D Mantovani A Gray P.W Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells.J. Exp. Med. 1997; 185: 1595-1604Crossref PubMed Scopus (405) Google Scholar, 35Sallusto F Palermo B Lenig D Miettinen M Matikainen S Julkunen I Forster R Burgstahler R Lipp M Lanzavecchia A Distinct patterns and kinetics of chemokine production regulate dendritic cell function.Eur. J. Immunol. 1999; 29 (a): 1617-1625Crossref PubMed Scopus (555) Google Scholar), and CCL19/MIP3β/ELC (29Ngo V.N Tang H.L Cyster J.G Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells.J. Exp. Med. 1998; 188: 181-191Crossref PubMed Scopus (392) Google Scholar, 35Sallusto F Palermo B Lenig D Miettinen M Matikainen S Julkunen I Forster R Burgstahler R Lipp M Lanzavecchia A Distinct patterns and kinetics of chemokine production regulate dendritic cell function.Eur. J. Immunol. 1999; 29 (a): 1617-1625Crossref PubMed Scopus (555) Google Scholar). Of these, probably the most dendritic specific is CCL17, which along with CCL22 signals through CCR4 (18Imai T Nagira M Takagi S Kakizaki M Nishimura M Wang J Gray P.W Matsushima K Yoshie O Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine.Int. Immunol. 1999; 11: 81-88Crossref PubMed Scopus (584) Google Scholar). In turn, this receptor has been associated with the Th2 phenotype (see below). In any case, these observations strongly suggest a role for chemokines in the initiation of immune responses and more specifically suggest that some chemokines may have adjuvant properties. The current data strongly suggests that dendritic cells can recruit various T cell subsets through their specific production of various chemokines. The chemokine receptors also exhibit strong specificity for dendritic cell subsets. Immature dendritic cells have been shown to express CCR6 and respond to CCL20/MIP3α/LARC in vitro (8Dieu M.C Vanbervliet B Vicari A Bridon J.M Oldham E Ait-Yahia S Briere F Zlotnik A Lebecque S Caux C Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites.J. Exp. Med. 1998; 188: 373-386Crossref PubMed Scopus (1185) Google Scholar). Once these cells pick up antigen, they start to mature and to express CCR7 (34Sallusto F Schaerli P Loetscher P Schaniel C Lenig D Mackay C.R Qin S Lanzavecchia A Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation.Eur. J. Immunol. 1998; 28: 2760-2769Crossref PubMed Scopus (936) Google Scholar), which has recently been shown to be pivotal for their migration to the lymph nodes (10Förster R Schubel A Breitfeld D Kremmer E Renner-Müller I Wolf E Lipp M CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs.Cell. 1999; 99: 23-33Abstract Full Text Full Text PDF PubMed Scopus (1819) Google Scholar). Dendritic cells can then respond to CCL19/MIP3β/ELC and CCL21/6Ckine/SLC, which allows them to migrate to the local draining lymph nodes, where they will be able to activate more antigen-specific T cells (20Kellermann S.A Hudak S Oldham E.R Liu Y.J McEvoy L.M The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3 beta are potent chemoattractants for in vitro- and in vivo-derived dendritic cells.J. Immunol. 1999; 162: 3859-3864PubMed Google Scholar). These studies and others (1Adema G.J Hartgers F Verstraten R de Vries E Marland G Menon S Foster J Xu Y Nooyen P McClanahan T et al.A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells.Nature. 1997; 387: 713-717Crossref PubMed Scopus (445) Google Scholar, 29Ngo V.N Tang H.L Cyster J.G Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells.J. Exp. Med. 1998; 188: 181-191Crossref PubMed Scopus (392) Google Scholar, 12Gunn M.D Kyuwa S Tam C Kakiuchi T Matsuzawa A Williams L.T Nakano H Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization.J. Exp. Med. 1999; 189: 451Crossref PubMed Scopus (871) Google Scholar, 35Sallusto F Palermo B Lenig D Miettinen M Matikainen S Julkunen I Forster R Burgstahler R Lipp M Lanzavecchia A Distinct patterns and kinetics of chemokine production regulate dendritic cell function.Eur. J. Immunol. 1999; 29 (a): 1617-1625Crossref PubMed Scopus (555) Google Scholar) strongly suggest that the production of chemokines by dendritic cells is not a random event, but rather a specific phenomenon that deserves further study to establish their function during immune responses. Another area where dendritic cells currently are being studied is for their role as potentiators of immune responses against tumors. Here, chemokines may also play an important role. XCL1/lymphotactin-transfected dendritic cells are better able to induce anti-tumor responses than the corresponding dendritic cells alone (7Cao X Zhang W He L Xie Z Ma S Tao Q Yu Y Hamada H Wang J Lymphotactin gene-modified bone marrow dendritic cells act as more potent adjuvants for peptide delivery to induce specific antitumor immunity.J. Immunol. 1998; 161: 6238-6244PubMed Google Scholar). For recent reviews on chemokines and tumors see 2Arenberg D.A Polverini P.J Kunkel S.L Shanafelt A Hesselgesser J Horuk R Strieter R.M The role of CXC chemokines in the regulation of angiogenesis in non-small cell lung cancer.J. Leukoc. Biol. 1997; 62: 554-562Crossref PubMed Google Scholar, and 41Wang J.M Deng X Gong W Su S Chemokines and their role in tumor growth and metastasis.J. Immunol. Methods. 1998; 220: 1-17Crossref PubMed Scopus (272) Google Scholar. A few years ago, nothing was known about a potential role of chemokines in lymphoid development. However, now there are several examples of chemokines involved in both B and T cell development. For example, the CXCL12/SDF-1−/− mouse dies perinatally and has a defect in B cell lymphopoiesis (26Nagasawa T Hirota S Tachibana K Takakura N Nishikawa S Kitamura Y Yoshida N Kikutani H Kishimoto T Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1.Nature. 1996; 382: 635-638Crossref PubMed Scopus (1940) Google Scholar). The defect may be due to defects in the bone marrow stromal microenvironment, which looks disorganized. The CXCR4−/− mouse also shows similar defects, suggesting that the only ligand of CXCR4 is CXCL12 (24Ma Q Jones D Borghesani P.R Segal R.A Nagasawa T Kishimoto T Bronson R.T Springer T.A Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice.Proc. Natl. Acad. Sci. USA. 1998; 95: 9448-9453Crossref PubMed Scopus (1381) Google Scholar, 38Tachibana K Hirota S Iizasa H Yoshida H Kawabata K Kataoka Y Kitamura Y Matsushima K Yoshida N Nishikawa S Kishimoto T Nagasawa T The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract.Nature. 1998; 393: 591-594Crossref PubMed Scopus (1285) Google Scholar, 47Zou Y.R Kottmann A.H Kuroda M Taniuchi I Littman D.R Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development.Nature. 1998; 393: 595-599Crossref PubMed Scopus (2057) Google Scholar). Chemokines may also be important in the thymic microenvironment. Several chemokines have been reported to be expressed during thymic development, including XCL1/lymphotactin, CCL3/MIP1α, CCL4/MIP1β (21Kelner G Zlotnik A Cytokine profile of early thymocytes and the characterization of a new class of chemokine.J. Leuk. Biol. 1995; 57: 778-781PubMed Google Scholar), CCL17/TARC (17Imai T Yoshida T Baba M Nishimura M Kakizaki M Yoshie O Molecular cloning of a novel T cell-directed CC chemokine expressed in thymus by signal sequence trap using Epstein-Barr virus vector.J. Biol. Chem. 1996; 271: 21514-21521Crossref PubMed Scopus (272) Google Scholar), CCL21/6ckine/SLC (5Campbell J.J Pan J Butcher E.C Cutting edge developmental switches in chemokine responses during T cell maturation.J. Immunol. 1999; 163 (a): 2353-2357PubMed Google Scholar), and CCL25/TECK (40Vicari A.P Figueroa D.J Hedrick J.A Foster J.S Singh K.P Menon S Copeland N.G Gilbert D.J Jenkins N.A Bacon K.B Zlotnik A TECK a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development.Immunity. 1997; 7: 291-301Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). Expression of the latter one has only been detected in the thymus, and, to a lesser extent, in the small intestine, an organ that is also believed to be a site of extrathymic development (40Vicari A.P Figueroa D.J Hedrick J.A Foster J.S Singh K.P Menon S Copeland N.G Gilbert D.J Jenkins N.A Bacon K.B Zlotnik A TECK a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development.Immunity. 1997; 7: 291-301Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). CCL25 is produced by thymic dendritic cells (40Vicari A.P Figueroa D.J Hedrick J.A Foster J.S Singh K.P Menon S Copeland N.G Gilbert D.J Jenkins N.A Bacon K.B Zlotnik A TECK a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development.Immunity. 1997; 7: 291-301Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar) as well as epithelial cells (42Wilkinson B Owen J.J Jenkinson E.J Factors regulating stem cell recruitment to the fetal thymus.J. Immunol. 1999; 162: 3873-3881PubMed Google Scholar). Recently, its receptor has been identified as the previously orphan receptor GPR9-6 and was therefore renamed CCR9 (44Zaballos A Gutierrez J Varona R Ardavin C Marquez G Cutting edge identification of the orphan chemokine receptor GPR-9–6 as CCR9, the receptor for the chemokine TECK.J. Immunol. 1999; 162: 5671-5675PubMed Google Scholar). Furthermore, it has been shown that immature thymocytes respond to CCL25, suggesting that CCL25 may be particularly important in early thymic development (5Campbell J.J Pan J Butcher E.C Cutting edge developmental switches in chemokine responses during T cell maturation.J. Immunol. 1999; 163 (a): 2353-2357PubMed Google Scholar). This differential responsiveness of thymocytes to chemokines indicates that thymocytes at different stages of development express different chemokine receptors. In turn, the signals that regulate the expression of these receptors may depend on having each thymocyte achieve specific “milestones” in its development (commitment to the T cell lineage, αβ versus γδ TCR rearrangement, β selection, and positive or negative selection). The current available information on CXCR4, CCR5, or CCR8 expression on thymocytes suggests that this is the c