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TREM-2: a novel link between dendritic-cell maturation and T-cell priming
10
News & Comment
TRENDS in Immunology Vol.23 No.1 January 2002
In Brief
TREM-2: a novel link between dendritic-cell maturation and T-cell priming Dendritic cells (DCs) are extremely potent at priming T-cell responses. However, whereas naive T cells recirculate between the blood, lymph nodes and spleen and do not usually enter peripheral tissues, a large proportion of DCs samples proteins and pathogens actively in the periphery but fails to enter primary lymphoid organs, where DCs would encounter naive T cells. It is only upon the activation of DCs, leading to the upregulation of expression of CC-chemokine receptor 7 (CCR7) – the same chemokine receptor that is expressed on naive T cells – that DCs migrate from the periphery to the T-cell regions of lymphoid organs. Thus, factors and events that influence the upregulation of expression of CCR7 and hence, the migration of DCs to lymphoid organs are key to the regulation of T-cell responses. Many factors of this kind have been identified and include host-derived proteins, such as CD40L, TNF and TRANCE/RANKL, as well as pathogen-derived molecules, such as LPS and DNA molecules rich in nonmethylated CpG motifs. In general, these factors induce the degradation of IκB and subsequent translocation of NF-κB into the nucleus of DCs, inducing the maturation program. Thus, the activation of NF-κB seems to be a key player in the regulation of the activation, maturation and migration of DCs. The paper by Bouchon et al. [1] identifies triggering receptor on myeloid cells 2 (TREM-2) as a novel factor involved in the regulation of DC maturation. TREM-2 is a recently identified TREM family member of the Ig superfamily. Stimulation of TREM-2 is shown to induce a distinct maturation program in DCs, leading to the up-regulation of expression of CCR7 and some costimulatory molecules, and prolonged cellular survival. However, in contrast to CD40L or LPS, TREM-2 fails to induce the up-regulation of expression of adhesion molecules, such as ICAM, and does not induce the down-regulation of expression of receptors involved in the capture of antigen, such as the mannose receptor. Moreover, in contrast to previously known activators of DCs, TREM-2 does not stimulate the NF-κB pathway or the stress-activated protein kinases (SAPK/p38 or JNK), but seems to operate exclusively through stimulation of http://immunology.trends.com
the MAP kinase ERK. Thus, TREM-2 induces a unique maturation program in DCs, most probably owing to selective activation of the ERK pathway. Interestingly, TREM-2 is shown to interact with the adapter molecule DAP12, which is known to recruit ZAP70 and p72/syk through its ITAM motifs. Thus, DAP12 relays TREM-2 signals to the ERK pathway and is probably responsible for the unique phenotype of TREM-2-activated DCs. The findings by Bouchon et al. have major implications for our understanding of the regulation of DC trafficking and induction of T-cell responses. First, it is becoming increasingly evident that the maturation of DCs is not an all or none event but might occur in several distinct ways, dependent upon the types of signaling pathways triggered within the cell. The present study indicates that the balance beween NF-κB and ERK signals might be of key importance for this process. Second, it is known that the DCs of DAP12-deficient mice fail to migrate to lymphoid organs from mucosal and epithelial tissues, and exhibit severely impaired Th1 responses. This suggests strongly an important role for TREM-2 in regulating T-cell responses in vivo. Third, recent evidence indicates that a proportion of mature DCs found in lymphoid organs is highly efficient at capturing antigens and processing them for MHC-class-I- and class-II-restricted presentation. Because DCs activated by TREM-2 up-regulate their expression of costimulatory molecules and CCR7, they would be perceived generally as fully mature cells. Nevertheless, these DCs maintain their high-level expression of receptors involved in antigen capture. Thus, TREM-2 might be involved in the normal turnover of DCs and might be responsible for the presence of mature DCs, fully capable of antigen processing, in lymphoid organs. A specific ligand for TREM-2 has not been discovered so far and the elucidation of its nature will be a major goal for the future. 1 Bouchon, A. et al. (2001) A DAP12-mediated pathway regulates expression of CC-chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 194, 1111–1122
Martin F. Bachmann [email protected]
Fish mast cells contain natural antibiotics
Researchers from North Carolina State University, USA have found an unusual source of natural antibiotics in fish. They isolated infection-fighting proteins, called peptide antibiotics, from the mast cells of aquacultured fish. Mast cells are known to participate in the untoward immune-system reactions observed during asthma and allergies. Their role in fighting disease has been viewed mainly as defending against parasites and helping to instruct other immune cells to kill infectious agents. If human mast cells produce such antibiotics also, it might be possible to use the chemicals to fight infection by manipulating their natural levels. Isolation of the antibiotics might also form the basis for developing new infectionfighting drugs. Nature (2001) 414, 268–269 SW
Fetal immune responses and brain damage Neuronal damage remains common in the preterm infant, despite the advent of modern intensive care. Measures of the levels of a number of proinflammatory cytokines (and IL-10), as well as the proportions of activated T cells, in the umbilical-cord blood of a series of 50 British infants of <29 weeks gestation showed patterns associated with brain damage in 18 cases. Infant brains were assessed using magnetic resonance imaging of the whole brain; lesions were detected in and around the ventricles, and in the caudate nucleus. Mothers of the children with brain damage often showed evidence of inflammatory immune responses also. Challenges remain to the clinical process of diagnosis of brain damage and promotion of optimal fetal brain development. Lancet (2001) 358, 1699 CM
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
News & Comment
TRENDS in Immunology Vol.23 No.1 January 2002
In Brief
TREM-2: a novel link between dendritic-cell maturation and T-cell priming Dendritic cells (DCs) are extremely potent at priming T-cell responses. However, whereas naive T cells recirculate between the blood, lymph nodes and spleen and do not usually enter peripheral tissues, a large proportion of DCs samples proteins and pathogens actively in the periphery but fails to enter primary lymphoid organs, where DCs would encounter naive T cells. It is only upon the activation of DCs, leading to the upregulation of expression of CC-chemokine receptor 7 (CCR7) – the same chemokine receptor that is expressed on naive T cells – that DCs migrate from the periphery to the T-cell regions of lymphoid organs. Thus, factors and events that influence the upregulation of expression of CCR7 and hence, the migration of DCs to lymphoid organs are key to the regulation of T-cell responses. Many factors of this kind have been identified and include host-derived proteins, such as CD40L, TNF and TRANCE/RANKL, as well as pathogen-derived molecules, such as LPS and DNA molecules rich in nonmethylated CpG motifs. In general, these factors induce the degradation of IκB and subsequent translocation of NF-κB into the nucleus of DCs, inducing the maturation program. Thus, the activation of NF-κB seems to be a key player in the regulation of the activation, maturation and migration of DCs. The paper by Bouchon et al. [1] identifies triggering receptor on myeloid cells 2 (TREM-2) as a novel factor involved in the regulation of DC maturation. TREM-2 is a recently identified TREM family member of the Ig superfamily. Stimulation of TREM-2 is shown to induce a distinct maturation program in DCs, leading to the up-regulation of expression of CCR7 and some costimulatory molecules, and prolonged cellular survival. However, in contrast to CD40L or LPS, TREM-2 fails to induce the up-regulation of expression of adhesion molecules, such as ICAM, and does not induce the down-regulation of expression of receptors involved in the capture of antigen, such as the mannose receptor. Moreover, in contrast to previously known activators of DCs, TREM-2 does not stimulate the NF-κB pathway or the stress-activated protein kinases (SAPK/p38 or JNK), but seems to operate exclusively through stimulation of http://immunology.trends.com
the MAP kinase ERK. Thus, TREM-2 induces a unique maturation program in DCs, most probably owing to selective activation of the ERK pathway. Interestingly, TREM-2 is shown to interact with the adapter molecule DAP12, which is known to recruit ZAP70 and p72/syk through its ITAM motifs. Thus, DAP12 relays TREM-2 signals to the ERK pathway and is probably responsible for the unique phenotype of TREM-2-activated DCs. The findings by Bouchon et al. have major implications for our understanding of the regulation of DC trafficking and induction of T-cell responses. First, it is becoming increasingly evident that the maturation of DCs is not an all or none event but might occur in several distinct ways, dependent upon the types of signaling pathways triggered within the cell. The present study indicates that the balance beween NF-κB and ERK signals might be of key importance for this process. Second, it is known that the DCs of DAP12-deficient mice fail to migrate to lymphoid organs from mucosal and epithelial tissues, and exhibit severely impaired Th1 responses. This suggests strongly an important role for TREM-2 in regulating T-cell responses in vivo. Third, recent evidence indicates that a proportion of mature DCs found in lymphoid organs is highly efficient at capturing antigens and processing them for MHC-class-I- and class-II-restricted presentation. Because DCs activated by TREM-2 up-regulate their expression of costimulatory molecules and CCR7, they would be perceived generally as fully mature cells. Nevertheless, these DCs maintain their high-level expression of receptors involved in antigen capture. Thus, TREM-2 might be involved in the normal turnover of DCs and might be responsible for the presence of mature DCs, fully capable of antigen processing, in lymphoid organs. A specific ligand for TREM-2 has not been discovered so far and the elucidation of its nature will be a major goal for the future. 1 Bouchon, A. et al. (2001) A DAP12-mediated pathway regulates expression of CC-chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 194, 1111–1122
Martin F. Bachmann [email protected]
Fish mast cells contain natural antibiotics
Researchers from North Carolina State University, USA have found an unusual source of natural antibiotics in fish. They isolated infection-fighting proteins, called peptide antibiotics, from the mast cells of aquacultured fish. Mast cells are known to participate in the untoward immune-system reactions observed during asthma and allergies. Their role in fighting disease has been viewed mainly as defending against parasites and helping to instruct other immune cells to kill infectious agents. If human mast cells produce such antibiotics also, it might be possible to use the chemicals to fight infection by manipulating their natural levels. Isolation of the antibiotics might also form the basis for developing new infectionfighting drugs. Nature (2001) 414, 268–269 SW
Fetal immune responses and brain damage Neuronal damage remains common in the preterm infant, despite the advent of modern intensive care. Measures of the levels of a number of proinflammatory cytokines (and IL-10), as well as the proportions of activated T cells, in the umbilical-cord blood of a series of 50 British infants of <29 weeks gestation showed patterns associated with brain damage in 18 cases. Infant brains were assessed using magnetic resonance imaging of the whole brain; lesions were detected in and around the ventricles, and in the caudate nucleus. Mothers of the children with brain damage often showed evidence of inflammatory immune responses also. Challenges remain to the clinical process of diagnosis of brain damage and promotion of optimal fetal brain development. Lancet (2001) 358, 1699 CM
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.