- Email: [email protected]
Cytokines and chemokines in T lymphopoiesis and T-cell effector function
TRENDS I M M U N O L O G Y T O D AY
Anniversary issue of Immunology Letters. For several years, including the past few decades, Polish science has been depressed by the political and economic situation. But today, it is possible to look forward to the next
millennium with trust for a better future for Polish immunology. Details of the EFIS 2000 program can be found at www.efis2000.pl
Andrzej Mackiewicz ([email protected]) is at the Dept of Cancer Immunology, University School of Medical Sciences at Great Poland Cancer Center, 15 Garbary St, 61866 Poznan, Poland.
EFIS
Cytokines and chemokines in T lymphopoiesis and T-cell effector function Paola Romagnani, Francesco Annunziato, Marie-Pierre Piccinni, Enrico Maggi and Sergio Romagnani Recent data on the role of cytokines,
T
he role of cytokines produced during T helper 1 (Th1)- or Th2-dominated specific immune responses in the pathogenesis of different pathological conditions has been widely recognized (reviewed in Ref. 1). In the past few years, it has become clear that T cells also express a large variety of chemokine receptors and respond to an impressive number of chemokines. In most cases, regulation of chemokine receptor expression depends upon the phenotype and consequent functional properties of the T cells2,3.
Chemokines and human T lymphopoiesis Chemokines have been shown to regulate differentiation-dependent thymocyte migration4–7. Macrophage-derived chemokine (MDC), produced in the human thymus by medullary thymic epithelial cells (TECs), attracts a subset of murine CD41CD8lo thymocytes7. In humans, MDCs attract a small subset of CD3hiCD41CD8lo thymocytes that express both CC chemokine receptor (CCR)4 and CD30. By contrast, EBI1-ligand chemokine (ELC) attracts CD41 or CD81 single-positive (SP) thymocytes expressing CD45RA, but not CD30 (Ref. 8). MDCproducing medullary TECs coincide with those previously found to express CD30 ligand (CD30L) (Ref. 9), but are distinct from ELC-producing medullary TECs (Ref. 8).
chemokines and/or chemokine receptors associated with T helper 1 (Th1) and Th2 cells have highlighted their role in T lymphopoiesis, proliferative glomerulonephritis, angiogenesis, infection, pregnancy and unexplained recurrent abortions, and atopy.
Because models of both CD30-deficient and CD30-transgenic mice support the concept that CD30–CD30L interactions might be involved in the process of negative selection10,11, these findings suggest that MDCproducing, CD30L-expressing, medullary TECs attract CCR4-expressing activated thymocytes that are targeted to programmed cell death. By contrast, ELC-producing medullary TECs attract CCR7-expressing CD41 or CD81 SP mature T cells, which have survived the negative selection process and can therefore colonize secondary lymphoid organs8. Of note, other subsets of medullary and subcapsular TECs were found to produce interferon (IFN)-inducible protein 10 (IP-10), monokine induced by IFN-g (Mig) and IFNinducible T-cell alpha chemoattractant (I-TAC). These chemokines favoured the migration of at least three distinct subsets
0167-5699/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
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of CXCR3-expressing human thymocytes, including mature T-cell receptor (TCR) abCD81 SP T cells, TCRgd T cells and natural killer cells (P. Romagnani et al., unpublished).
Cytokines, chemokines and their receptors in T-cell effector functions CXCR3 and GN CXCR3, a chemokine receptor preferentially associated with Th1 cells12, is highly expressed in kidneys of patients with proliferative glomerulonephritis (GN), as well as in cultured human mesangial cells (HMCs), but poorly or not at all in normal kidneys or kidneys of patients with nonproliferative GN (Ref. 13). Moreover, the CXCR3 ligands, IP-10 and Mig, induce intracellular Ca21 influx and thymidine incorporation by HMCs (Ref. 13). More recently, high expression of IP-10 and Mig was found in both infiltrating mononuclear cells and resident glomerular cells of kidneys from patients with proliferative GN (P. Romagnani et al., unpublished), providing support for the possibility that Th1 responses play a pathogenic role in this disease14.
Angiostatic activity of CXCR3-binding chemokines Despite many studies, the nature of receptors for angiostatic chemokines on endothelial cells (ECs) is still controversial15. PII: S0167-5699(00)01670-4
TRENDS I M M U N O L O G Y TO D AY
Nevertheless, CXCR3 expression has been detected in some ECs present in biopsy specimens of normal or pathological kidney, liver and thyroid tissue. CXCR3 was also expressed by cultured human microvascular ECs (HMVECs), but only in the S/G2–M phase of their cycle. Moreover, IP-10, Mig and I-TAC acted as effective inhibitors of HMVEC proliferation, suggesting that their angiostatic effect may be mediated by the interaction with CXCR3 expressed by ECs when they enter into the proliferative phase (P. Romagnani et al., unpublished).
Chemokine receptors and HIV-1 CCR5 and CXCR4 act as co-receptors for the entry into CD41 T cells of M-tropic (now R5-tropic) and T-cell-line-tropic (now X4tropic) HIV-1 strains, respectively16,17. Although CCR5 is preferentially associated with Th1 cells, whereas CXCR4 is expressed by both Th1 and Th2 cells, and even by naive Th cells, Th2 cells have been found to support the expression of both R5- and X4-tropic HIV-1 strains better than Th1 cells18. Major expression of X4-tropic HIV-1 strains in Th2 cells results from higher viral entry owing to upregulation by interleukin 4 (IL-4), and downregulation by IFN-g, of CXCR4 expression19,20. As expected, R5-tropic HIV-1 strains were found to enter better into Th1 cells soon after the infection; however, subsequent viral spread among Th1 cells was blocked by the ability of these cells to produce high amounts of CCR5-binding chemokines, which compete with HIV-1 for T-cell entry21.
Th2 cytokines and LIF in pregnancy T-cell clones generated from the decidua of women suffering from unexplained recurrent abortions (URA) exhibit reduced production of Th2 cytokines, IL-4, IL-10 and leukaemia inhibitory factor (LIF), in comparison with T-cell clones generated from the decidua of women following voluntary abortion22. T-cell clones generated from T cells of the cumulus oophorus of women undergoing artificial insemination showed the potential to produce high amounts of IL-4, IL-5, IL-10 and LIF. More importantly, deficient LIF mRNA expression was found in decidual specimens of women
suffering from URA in comparison with fertile women (M-P. Piccinni et al., unpublished).
anti-CRTH2 mAb; and M. Uguccioni (Theodor Kocher Institute, Bern, Switzerland) for providing the anti-CXCR3 mAb.
New markers for the detection of type 2 T-cell responses in vivo MDC was found to be produced not only by macrophages and dendritic cells but also by T cells, mainly belonging to the Th2 subset23. Accordingly, high levels of MDC were found in the serum of patients with atopic dermatitis, and MDC-producing cells could be detected in the skin of the same patients23. By assessing the expression on circulating T cells of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2)24, elevated numbers of circulating Th2 and type 2 cytotoxic (Tc2) CD81 T cells were found in atopic dermatitis, as well as in advanced HIV infection25. Comparison with CCR3 and CCR4 revealed that CRTH2 is the most reliable, and probably the only selective, surface marker for the identification of both human Th2 and Tc2 cells in vivo. CCR4 was indeed expressed not only on Th2 but also on Th0 cells, and CCR3 was virtually undectable on T cells25 despite the fact that the same anti-CCR3 monoclonal antibody revealed high CCR3 expression on both human basophils and mast cells26.
Conclusion The results of these studies provide additional support for the role of cytokines and chemokines, as well as their receptors, in Th1 or Th2 responses in several human physiological or pathological conditions. It is noteworthy that the same cytokines and/or chemokines may play different and, in some cases, opposite functions during the process of cell development and differentiation, or in the context of inflammed tissues in pathological conditions.
The experiments reported in this paper were performed by grants provided by AIRC, ISS (AIDS project) and MURST. The authors wish to thank: W. Newmann (Leukosite, Cambridge, MA) for providing the anti-CCR3 mAb; D. Chantry (Icos Corporation, Bothell, WA) for providing the antiCCR4, anti-MDC and anti-ELC mAbs; K. Nagata (R & D Center, Saitama, Japan) for providing the
Paola Romagnani is at the Dept of Physiopathology, Endocrinology Unit, University of Florence, Italy; Francesco Annunziato, Marie-Pierre Piccinni, Enrico Maggi and Sergio Romagnani ([email protected]) are at the Dept of Internal Medicine, University of Florence, 50134, Italy. References 1 Romagnani, S. (1997) The Th1/Th2 paradigm. Immunol. Today 18, 263–266 2 Baggiolini, M. (1998) Chemokines and leukocyte traffic. Nature 392, 565–568 3 Ward, S.G. et al. (1998) Chemokines and T lymphocytes: more than an attraction. Immunity 9, 1–11 4 Kim, C.H. et al. (1998) Differential chemotactic behavior of developing T cells in response to thymic chemokines. Blood 91, 4434–4443 5 Campbell, J.J. et al. (1999) Developmental switches in chemokine responses during T cell maturation. J. Immunol. 163, 2353–2357 6 Zabel, B.A. et al. (1999) Human G proteincoupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokinemediated chemotaxis. J. Exp. Med. 190, 1241–1255 7 Chantry, D. et al. (1999) Macrophage derived chemokine (MDC) is localized to thymic medullary epithelial cells and is a chemoattractant for CD31, CD41, CD8low thymocytes. Blood 94, 1890–1898 8 Annunziato, F. et al. (2000) Macrophagederived chemokine and EBI1-ligand chemokine attract human thymocytes in different stage of development and are produced by distinct subsets of medullary epithelial cells: possible implications for negative selection. J. Immunol. 165, 238–246 9 Romagnani, P. et al. (1998) High CD30 ligand expression by epithelial cells and Hassal’s corpuscles in the medulla of human thymus. Blood 91, 3323–3332 10 Amakawa, R. et al. (1996). Impaired negative selection of T cells in Hodgkin’s disease antigen CD30-deficient mice. Cell 84, 551–562 11 Chiarle, R. et al. (1999) CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway. J. Immunol. 163, 194–205 12 Bonecchi, R. et al. (1998) Differential expression of chemokine receptors and
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chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med. 187, 129–134 Romagnani, P. et al. (1999) Role for interactions between IP-10/Mig and CXCR3 in proliferative glomerulonephritis. J. Am. Soc. Nephrol. 10, 2518–2526 Holdsworth, S.R. et al. (1999) Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis. Kidney Int. 55, 1198–1216 Keane, M.P. and Strieter, R.M. (1999) The role of CXC chemokines in the regulation of angiogenesis. Chem. Immunol. 72, 86–101 Dragic, T. et al. (1996) HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673 Feng, Y. et al. (1996) HIV-1 entry cofactor: functional cDNA cloning of a seventransmembrane G protein-coupled receptor. Science 272, 872–877
18 Maggi, E. et al. (1994) Ability of HIV-1 to promote a Th1 to Th0 shift and to replicate preferentially in Th2 and Th0 cells. Science 265, 244–248 19 Jordan, P. et al. (1998) IL-4 induces functional cell-surface expression of CXCR4 on human T cells. J. Immunol. 160, 4153–4157 20 Galli, G. et al. (1998) Enhanced HIV expression during T helper 2-oriented responses due to the opposite regulatory effect of IL-4 and IFN-g on fusin/CXCR4. Eur. J. Immunol. 28, 3280–3290 21 Annunziato, F. et al. (2000) Limited expression of R5-tropic HIV-1 in CCR5positive Th1-polarized T cells explained by their ability to produce RANTES, MIP-1a, and MIP-1b. Blood 95, 1167–1174 22 Piccinni, M-P. et al. (1998) Role of type 2 T helper (Th2) cytokines and leukemia inhibitory factor (LIF) produced by decidual T cells in the development
23
24
25
26
and maintenance of successful pregnancy. Nat. Med. 4, 1020–1024 Galli, G. et al. (2000) Macrophage-derived chemokine production by activated human T cells in vitro and in vivo: preferential association with the production of type 2 cytokines. Eur. J. Immunol. 204–210 Nagata, K. et al. (1999) Selective expression of a novel surface molecule by human Th2 cells in vivo. J. Immunol. 162, 1278–1286 Cosmi, L. et al. CRTH2 is the most reliable marker for the detection of circulatory human type 2 Th (Th2) and type 2 T cytotoxic (Tc2) cells in health and disease. Eur. J. Immunol. (in press) Romagnani, P. et al. (1999) Tryptase–chymase double positive human mast cells express the eotaxin receptor CCR3 and are attracted by CCR3-binding chemokines. Am. J. Pathol. 155, 1195–1204
EFIS
Chemokines in inflammation and immunity Marco Baggiolini and Pius Loetscher Since the discovery of interleukin 8 (IL-8), about 50 chemokines have
C
hemokines are chemotaxisinducing proteins of 70–130 amino acids that are secreted by leukocytes or tissue cells. These small proteins act on leukocytes via hepathelical receptors coupled to Bordetella pertussis toxin sensitive G proteins. They have four conserved cysteine residues linked by disulfide bonds. Sequence motifs in the vicinity of the first two cysteine residues determine receptor recognition and triggering. The disulfide bonds keep these functional domains in close proximity and are thus essential for biological activity. Modification of the N-terminal region by truncation or amino acid substitution markedly influences chemokine activity. Several chemokine receptor antagonists have been obtained in this manner. For further information on chemokines, see reviews in Refs 1–7. Interleukin 8 (IL-8) and many other chemokines are induced in different types of cells by inflammatory cytokines, microbial toxins and other conditions that disturb homeostasis. They are generally
been characterized. Originally, they were considered as inducible mediators of inflammation, but in recent years, several chemokines have been identified that are expressed constitutively and function in the physiological traffic and homing of leukocytes.
called inflammatory chemokines. Clusters of inflammatory chemokines share receptors and have common functional activities (Fig. 1). Redundancy is high, which is typical for mediators of inflammation and host defense.
Chemokine activities on lymphocytes In the past few years, lymphocyte traffic and homing became a major focus of chemokine
0167-5699/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
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research. It was found that T cells can express most known chemokine receptors and that expression depends on maturation, activation and functional differentiation. For instance, treatment of freshly isolated blood T cells with IL-2 induces the expression of CCR1, CCR2, CCR5 and CXCR3, and the cells thus become responsive to the appropriate inflammatory chemokines8–10. These receptors are rapidly downregulated by stimulation with anti-CD3 and anti-CD28, which mimics the encounter with an antigen. The upregulation of receptors for inflammatory chemokines after clonal expansion in response to IL-2 may prepare antigen-primed effector cells for recruitment to sites of immune intervention. The assumption that chemokine receptor expression may relate to function prompted studies on T helper 1 (Th1) and Th2 cells aimed at defining surface markers for helper cell subsets. Analysis of mRNA expression and flow cytometry showed that CCR5 is characteristic for Th1 cells and that CCR3 is characteristic for Th2 cells11–14. Immunohistochemical staining of inflamed tissues PII: S0167-5699(00)01672-8
Anniversary issue of Immunology Letters. For several years, including the past few decades, Polish science has been depressed by the political and economic situation. But today, it is possible to look forward to the next
millennium with trust for a better future for Polish immunology. Details of the EFIS 2000 program can be found at www.efis2000.pl
Andrzej Mackiewicz ([email protected]) is at the Dept of Cancer Immunology, University School of Medical Sciences at Great Poland Cancer Center, 15 Garbary St, 61866 Poznan, Poland.
EFIS
Cytokines and chemokines in T lymphopoiesis and T-cell effector function Paola Romagnani, Francesco Annunziato, Marie-Pierre Piccinni, Enrico Maggi and Sergio Romagnani Recent data on the role of cytokines,
T
he role of cytokines produced during T helper 1 (Th1)- or Th2-dominated specific immune responses in the pathogenesis of different pathological conditions has been widely recognized (reviewed in Ref. 1). In the past few years, it has become clear that T cells also express a large variety of chemokine receptors and respond to an impressive number of chemokines. In most cases, regulation of chemokine receptor expression depends upon the phenotype and consequent functional properties of the T cells2,3.
Chemokines and human T lymphopoiesis Chemokines have been shown to regulate differentiation-dependent thymocyte migration4–7. Macrophage-derived chemokine (MDC), produced in the human thymus by medullary thymic epithelial cells (TECs), attracts a subset of murine CD41CD8lo thymocytes7. In humans, MDCs attract a small subset of CD3hiCD41CD8lo thymocytes that express both CC chemokine receptor (CCR)4 and CD30. By contrast, EBI1-ligand chemokine (ELC) attracts CD41 or CD81 single-positive (SP) thymocytes expressing CD45RA, but not CD30 (Ref. 8). MDCproducing medullary TECs coincide with those previously found to express CD30 ligand (CD30L) (Ref. 9), but are distinct from ELC-producing medullary TECs (Ref. 8).
chemokines and/or chemokine receptors associated with T helper 1 (Th1) and Th2 cells have highlighted their role in T lymphopoiesis, proliferative glomerulonephritis, angiogenesis, infection, pregnancy and unexplained recurrent abortions, and atopy.
Because models of both CD30-deficient and CD30-transgenic mice support the concept that CD30–CD30L interactions might be involved in the process of negative selection10,11, these findings suggest that MDCproducing, CD30L-expressing, medullary TECs attract CCR4-expressing activated thymocytes that are targeted to programmed cell death. By contrast, ELC-producing medullary TECs attract CCR7-expressing CD41 or CD81 SP mature T cells, which have survived the negative selection process and can therefore colonize secondary lymphoid organs8. Of note, other subsets of medullary and subcapsular TECs were found to produce interferon (IFN)-inducible protein 10 (IP-10), monokine induced by IFN-g (Mig) and IFNinducible T-cell alpha chemoattractant (I-TAC). These chemokines favoured the migration of at least three distinct subsets
0167-5699/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
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of CXCR3-expressing human thymocytes, including mature T-cell receptor (TCR) abCD81 SP T cells, TCRgd T cells and natural killer cells (P. Romagnani et al., unpublished).
Cytokines, chemokines and their receptors in T-cell effector functions CXCR3 and GN CXCR3, a chemokine receptor preferentially associated with Th1 cells12, is highly expressed in kidneys of patients with proliferative glomerulonephritis (GN), as well as in cultured human mesangial cells (HMCs), but poorly or not at all in normal kidneys or kidneys of patients with nonproliferative GN (Ref. 13). Moreover, the CXCR3 ligands, IP-10 and Mig, induce intracellular Ca21 influx and thymidine incorporation by HMCs (Ref. 13). More recently, high expression of IP-10 and Mig was found in both infiltrating mononuclear cells and resident glomerular cells of kidneys from patients with proliferative GN (P. Romagnani et al., unpublished), providing support for the possibility that Th1 responses play a pathogenic role in this disease14.
Angiostatic activity of CXCR3-binding chemokines Despite many studies, the nature of receptors for angiostatic chemokines on endothelial cells (ECs) is still controversial15. PII: S0167-5699(00)01670-4
TRENDS I M M U N O L O G Y TO D AY
Nevertheless, CXCR3 expression has been detected in some ECs present in biopsy specimens of normal or pathological kidney, liver and thyroid tissue. CXCR3 was also expressed by cultured human microvascular ECs (HMVECs), but only in the S/G2–M phase of their cycle. Moreover, IP-10, Mig and I-TAC acted as effective inhibitors of HMVEC proliferation, suggesting that their angiostatic effect may be mediated by the interaction with CXCR3 expressed by ECs when they enter into the proliferative phase (P. Romagnani et al., unpublished).
Chemokine receptors and HIV-1 CCR5 and CXCR4 act as co-receptors for the entry into CD41 T cells of M-tropic (now R5-tropic) and T-cell-line-tropic (now X4tropic) HIV-1 strains, respectively16,17. Although CCR5 is preferentially associated with Th1 cells, whereas CXCR4 is expressed by both Th1 and Th2 cells, and even by naive Th cells, Th2 cells have been found to support the expression of both R5- and X4-tropic HIV-1 strains better than Th1 cells18. Major expression of X4-tropic HIV-1 strains in Th2 cells results from higher viral entry owing to upregulation by interleukin 4 (IL-4), and downregulation by IFN-g, of CXCR4 expression19,20. As expected, R5-tropic HIV-1 strains were found to enter better into Th1 cells soon after the infection; however, subsequent viral spread among Th1 cells was blocked by the ability of these cells to produce high amounts of CCR5-binding chemokines, which compete with HIV-1 for T-cell entry21.
Th2 cytokines and LIF in pregnancy T-cell clones generated from the decidua of women suffering from unexplained recurrent abortions (URA) exhibit reduced production of Th2 cytokines, IL-4, IL-10 and leukaemia inhibitory factor (LIF), in comparison with T-cell clones generated from the decidua of women following voluntary abortion22. T-cell clones generated from T cells of the cumulus oophorus of women undergoing artificial insemination showed the potential to produce high amounts of IL-4, IL-5, IL-10 and LIF. More importantly, deficient LIF mRNA expression was found in decidual specimens of women
suffering from URA in comparison with fertile women (M-P. Piccinni et al., unpublished).
anti-CRTH2 mAb; and M. Uguccioni (Theodor Kocher Institute, Bern, Switzerland) for providing the anti-CXCR3 mAb.
New markers for the detection of type 2 T-cell responses in vivo MDC was found to be produced not only by macrophages and dendritic cells but also by T cells, mainly belonging to the Th2 subset23. Accordingly, high levels of MDC were found in the serum of patients with atopic dermatitis, and MDC-producing cells could be detected in the skin of the same patients23. By assessing the expression on circulating T cells of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2)24, elevated numbers of circulating Th2 and type 2 cytotoxic (Tc2) CD81 T cells were found in atopic dermatitis, as well as in advanced HIV infection25. Comparison with CCR3 and CCR4 revealed that CRTH2 is the most reliable, and probably the only selective, surface marker for the identification of both human Th2 and Tc2 cells in vivo. CCR4 was indeed expressed not only on Th2 but also on Th0 cells, and CCR3 was virtually undectable on T cells25 despite the fact that the same anti-CCR3 monoclonal antibody revealed high CCR3 expression on both human basophils and mast cells26.
Conclusion The results of these studies provide additional support for the role of cytokines and chemokines, as well as their receptors, in Th1 or Th2 responses in several human physiological or pathological conditions. It is noteworthy that the same cytokines and/or chemokines may play different and, in some cases, opposite functions during the process of cell development and differentiation, or in the context of inflammed tissues in pathological conditions.
The experiments reported in this paper were performed by grants provided by AIRC, ISS (AIDS project) and MURST. The authors wish to thank: W. Newmann (Leukosite, Cambridge, MA) for providing the anti-CCR3 mAb; D. Chantry (Icos Corporation, Bothell, WA) for providing the antiCCR4, anti-MDC and anti-ELC mAbs; K. Nagata (R & D Center, Saitama, Japan) for providing the
Paola Romagnani is at the Dept of Physiopathology, Endocrinology Unit, University of Florence, Italy; Francesco Annunziato, Marie-Pierre Piccinni, Enrico Maggi and Sergio Romagnani ([email protected]) are at the Dept of Internal Medicine, University of Florence, 50134, Italy. References 1 Romagnani, S. (1997) The Th1/Th2 paradigm. Immunol. Today 18, 263–266 2 Baggiolini, M. (1998) Chemokines and leukocyte traffic. Nature 392, 565–568 3 Ward, S.G. et al. (1998) Chemokines and T lymphocytes: more than an attraction. Immunity 9, 1–11 4 Kim, C.H. et al. (1998) Differential chemotactic behavior of developing T cells in response to thymic chemokines. Blood 91, 4434–4443 5 Campbell, J.J. et al. (1999) Developmental switches in chemokine responses during T cell maturation. J. Immunol. 163, 2353–2357 6 Zabel, B.A. et al. (1999) Human G proteincoupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokinemediated chemotaxis. J. Exp. Med. 190, 1241–1255 7 Chantry, D. et al. (1999) Macrophage derived chemokine (MDC) is localized to thymic medullary epithelial cells and is a chemoattractant for CD31, CD41, CD8low thymocytes. Blood 94, 1890–1898 8 Annunziato, F. et al. (2000) Macrophagederived chemokine and EBI1-ligand chemokine attract human thymocytes in different stage of development and are produced by distinct subsets of medullary epithelial cells: possible implications for negative selection. J. Immunol. 165, 238–246 9 Romagnani, P. et al. (1998) High CD30 ligand expression by epithelial cells and Hassal’s corpuscles in the medulla of human thymus. Blood 91, 3323–3332 10 Amakawa, R. et al. (1996). Impaired negative selection of T cells in Hodgkin’s disease antigen CD30-deficient mice. Cell 84, 551–562 11 Chiarle, R. et al. (1999) CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway. J. Immunol. 163, 194–205 12 Bonecchi, R. et al. (1998) Differential expression of chemokine receptors and
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chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med. 187, 129–134 Romagnani, P. et al. (1999) Role for interactions between IP-10/Mig and CXCR3 in proliferative glomerulonephritis. J. Am. Soc. Nephrol. 10, 2518–2526 Holdsworth, S.R. et al. (1999) Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis. Kidney Int. 55, 1198–1216 Keane, M.P. and Strieter, R.M. (1999) The role of CXC chemokines in the regulation of angiogenesis. Chem. Immunol. 72, 86–101 Dragic, T. et al. (1996) HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673 Feng, Y. et al. (1996) HIV-1 entry cofactor: functional cDNA cloning of a seventransmembrane G protein-coupled receptor. Science 272, 872–877
18 Maggi, E. et al. (1994) Ability of HIV-1 to promote a Th1 to Th0 shift and to replicate preferentially in Th2 and Th0 cells. Science 265, 244–248 19 Jordan, P. et al. (1998) IL-4 induces functional cell-surface expression of CXCR4 on human T cells. J. Immunol. 160, 4153–4157 20 Galli, G. et al. (1998) Enhanced HIV expression during T helper 2-oriented responses due to the opposite regulatory effect of IL-4 and IFN-g on fusin/CXCR4. Eur. J. Immunol. 28, 3280–3290 21 Annunziato, F. et al. (2000) Limited expression of R5-tropic HIV-1 in CCR5positive Th1-polarized T cells explained by their ability to produce RANTES, MIP-1a, and MIP-1b. Blood 95, 1167–1174 22 Piccinni, M-P. et al. (1998) Role of type 2 T helper (Th2) cytokines and leukemia inhibitory factor (LIF) produced by decidual T cells in the development
23
24
25
26
and maintenance of successful pregnancy. Nat. Med. 4, 1020–1024 Galli, G. et al. (2000) Macrophage-derived chemokine production by activated human T cells in vitro and in vivo: preferential association with the production of type 2 cytokines. Eur. J. Immunol. 204–210 Nagata, K. et al. (1999) Selective expression of a novel surface molecule by human Th2 cells in vivo. J. Immunol. 162, 1278–1286 Cosmi, L. et al. CRTH2 is the most reliable marker for the detection of circulatory human type 2 Th (Th2) and type 2 T cytotoxic (Tc2) cells in health and disease. Eur. J. Immunol. (in press) Romagnani, P. et al. (1999) Tryptase–chymase double positive human mast cells express the eotaxin receptor CCR3 and are attracted by CCR3-binding chemokines. Am. J. Pathol. 155, 1195–1204
EFIS
Chemokines in inflammation and immunity Marco Baggiolini and Pius Loetscher Since the discovery of interleukin 8 (IL-8), about 50 chemokines have
C
hemokines are chemotaxisinducing proteins of 70–130 amino acids that are secreted by leukocytes or tissue cells. These small proteins act on leukocytes via hepathelical receptors coupled to Bordetella pertussis toxin sensitive G proteins. They have four conserved cysteine residues linked by disulfide bonds. Sequence motifs in the vicinity of the first two cysteine residues determine receptor recognition and triggering. The disulfide bonds keep these functional domains in close proximity and are thus essential for biological activity. Modification of the N-terminal region by truncation or amino acid substitution markedly influences chemokine activity. Several chemokine receptor antagonists have been obtained in this manner. For further information on chemokines, see reviews in Refs 1–7. Interleukin 8 (IL-8) and many other chemokines are induced in different types of cells by inflammatory cytokines, microbial toxins and other conditions that disturb homeostasis. They are generally
been characterized. Originally, they were considered as inducible mediators of inflammation, but in recent years, several chemokines have been identified that are expressed constitutively and function in the physiological traffic and homing of leukocytes.
called inflammatory chemokines. Clusters of inflammatory chemokines share receptors and have common functional activities (Fig. 1). Redundancy is high, which is typical for mediators of inflammation and host defense.
Chemokine activities on lymphocytes In the past few years, lymphocyte traffic and homing became a major focus of chemokine
0167-5699/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved.
S E P T E M B E R 418
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research. It was found that T cells can express most known chemokine receptors and that expression depends on maturation, activation and functional differentiation. For instance, treatment of freshly isolated blood T cells with IL-2 induces the expression of CCR1, CCR2, CCR5 and CXCR3, and the cells thus become responsive to the appropriate inflammatory chemokines8–10. These receptors are rapidly downregulated by stimulation with anti-CD3 and anti-CD28, which mimics the encounter with an antigen. The upregulation of receptors for inflammatory chemokines after clonal expansion in response to IL-2 may prepare antigen-primed effector cells for recruitment to sites of immune intervention. The assumption that chemokine receptor expression may relate to function prompted studies on T helper 1 (Th1) and Th2 cells aimed at defining surface markers for helper cell subsets. Analysis of mRNA expression and flow cytometry showed that CCR5 is characteristic for Th1 cells and that CCR3 is characteristic for Th2 cells11–14. Immunohistochemical staining of inflamed tissues PII: S0167-5699(00)01672-8