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Successful skin grafts carry persuasive passengers
News & Comment
These results are important because they provide evidence that IL-2 acts through third-party cells, specifically CD4+CD25+ regulatory cells, to inhibit the survival of CD8+ memory T cells. It will be interesting to see if CD4+CD25+ regulatory cells provide a mechanism for IL-2 to affect the activity of other immune cells, such as activated T cells or even non-T cells. If so, this would
TRENDS in Immunology Vol.23 No.9 September 2002
describe a rational strategy of immune regulation, in which the immune-promoting effects of sustained and high levels of IL-2 are counterbalanced by the inhibitory effects of IL-2-sensitive regulatory T cells. Thus, the results from Murakami et al. provide crucial insight into the mechanisms that might underlie the paradoxical effects of IL-2 on the immune response.
431
1 Murakami, M. et al. (2002) CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc. Natl. Acad. Sci. U. S. A. 99, 8832–8837
Mark P. Rubinstein [email protected] Mark I. Block [email protected]
Respectability for regulatory T cells Like a favorite aunt returning from exotic travels to marry the local vicar, regulatory T (Tr) cells have overcome their former notoriety and entered a new era of respectability. Following the original description of CD4+CD25+ Tr cells, studies of this regulatory subset have been gathering momentum. A recent paper has provided answers to several outstanding questions and offers a new framework within which to think about the differentiation of Tr cells and the generation of tolerance. Apostolou et al. [1] used a murine model in which animals bearing a transgenic T-cell receptor (TCR) specific for an influenza hemagglutinin (HA) peptide were exposed to cells expressing HA under the control of the Igκ promoter. T cells isolated from double transgenics displayed features of Tr cells. They secreted interleukin (IL)-10, expressed high levels of the negative costimulators, CTLA-4 and PD-1, failed to proliferate upon antigen challenge and, most importantly, inhibited the responses
of other T cells with specificity for the same antigen. Interestingly, these Tr cells included both CD25+ or CD25− subsets, which appeared functionally equivalent. The CD25 phenotype of the Tr cell depended on the cells that initially presented the tolerizing HA. Presentation of the antigen on the surface of a thymic epithelial cell resulted primarily in the generation of CD4+CD25+ Tr cells, whereas expression of HA on (unactivated) bone marrow-derived cells resulted predominantly in the generation of CD4+CD25− Tr cells. These experiments also revealed that Tr cells can be generated both intrathymically, by high affinity TCR interactions in the thymic cortex, and extrathymically, from naïve, but functionally mature, T cells. This work closely parallels other studies in which the same antigen was expressed under the control of the SV40 rather than the Igκ promoter. With the SV40 promoter, Tr-cell function strictly segregates with the CD25+ phenotype, lending further support
to the notion that the nature of the cells on which the HA antigen is presented, and/or its expression density, might influence the CD25 phenotype of Tr cells. In neither study is the precise nature of the relevant antigen-presenting cell defined. The mechanism by which T cells are stimulated to differentiate along a regulatory rather than a more conventional helper T-cell path also remains a mystery. However, given the current level of interest in Tr cells, the answers to these and other questions regarding them will soon be found. 1 Apostolou, I. et al. (2002) Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 10.1038/ni816 (http://www.nature.com/ni/)
Judy Owen [email protected] Jennifer Punt [email protected]
Successful skin grafts carry persuasive passengers Therapeutic induction of peripheral tolerance is known to involve at least two phenomena: dominant tolerance, whereby pre-existing regulatory T (Tr) cells disarm non-tolerant naïve cells, and infectious tolerance, whereby novel regulatory cells emerge from the naïve-lymphocyte population. Although it is apparent from many murine studies that the cells mediating dominant tolerance are CD4+, little further characterization of the cells has been performed. In particular, whether the active cells are related to the populations of CD4+CD25+ Tr cells, which are proposed to be the principal exponents of protection against autoimmune disease, has not been explored. Furthermore, it is not known if http://immunology.trends.com
CD4+ regulatory cells circulate through tolerated grafts because they have only been detected thus far in lymphoid tissues. Luis Graca et al. addressed these issues in two recent publications [1,2]. Their first paper examines the functional characteristics of CD4+CD25+/− Tr cells [1]. Dominant tolerance was initiated in CBA strain mice receiving allogeneic (B10.BR strain) skin grafts by treatment with non-depleting monoclonal antibodies to CD4 and CD8 at the time of transplantation. When transferred to ‘empty’ (i.e. thymectomized and T-cell depleted) CBA mice, the CD4+ Tr cells induced by this regimen failed to reject new B10.BR grafts and indeed could
abrogate rejection by co-transferred naïve (i.e. non-tolerant) cells. Both CD4+CD25+ and CD4+CD25− cells had the capacity to mediate dominant tolerance, although CD25+ cells were ~10-times more potent. A clear difference in the phenotype of the two cell populations was further highlighted by serial analysis of gene expression: activated CD4+CD25+ cells expressed ≥103 new transcripts, many of them unique and not yet assigned to known genes. The dominant regulatory cells implicated in this paper were isolated from the spleens of tolerant mice [1]. Graca et al. then used the same grafting model to investigate the presence of these cells within tolerated skin grafts [2].
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
432
News & Comment
The procedure involved an additional step: B10.BR skin that had previously been grafted to, and tolerated by, CBA mice was collected and re-grafted to ‘empty’ CBA mice. After 30 days, a second B10.BR skin graft was applied, with or without concurrent administration of naïve lymphocytes. The original graft was shown to carry ‘passenger’ CD4+CD25+/− Tr cells, which could prevent naïve cell-mediated rejection of the second graft. Additionally, the use of RAG1−/− mice as graft recipients showed that the T cells could expand from the grafted skin to peripheral blood and evoke regulatory function. However, despite the presence of Tr cells peripherally and in lymphoid organs, Zelenika et al.
TRENDS in Immunology Vol.23 No.9 September 2002
found their activity to be concentrated in the graft [3], suggesting that perhaps regulatory cells recirculate through the body, but accumulate and exert clinically evident effects at sites where their target antigens are present. Careful use of control groups established that T-cell regulatory function was not an artifact of the sorting procedure (indeed, unsorted cells showed greater tolerizing potency) [1], tolerant animals were not immunosuppressed and tolerance was not a result of microchimerism but, instead, was entirely reliant on T cells residing within, and then expanding from, the tolerated skin [2]. The role of CD4+CD25+/− Tr cells in mediating
transplantation tolerance will undoubtedly receive much further attention, particularly given the high demand for overcoming organ rejection in clinical settings. 1 Graca, L. et al. (2002) Both CD4+CD25+ and CD4+CD25− regulatory cells mediate dominant transplantation tolerance. J. Immunol. 168, 5558–5567 2 Graca, L. et al. (2002) Identification of regulatory T cells in tolerated allografts. J. Exp. Med. 195, 1641–1646 3 Zelenika, D. et al. (2002) Regulatory T cells overexpress a subset of Th2 gene transcripts. J. Immunol. 168, 1069–1079
Sarah Hudson Keenihan [email protected]
In Brief
A place for TACE in inflammatory bowel disease Tumour necrosis factor (TNF)-α has a central pathogenic role in inflammatory bowel disease (IBD). During local and systemic inflammatory reactions, membrane-bound TNF-α is cleaved extracellularly by a specific zinc metalloprotease, termed TNF-α-converting enzyme (TACE). This yields the soluble form of TNF-α that acts as a compartmentalized or circulating cytokine. It was originally thought that cleaved TNF-α was the major biological active form, but membraneexpressed TNF-α is biologically active. Researchers in Denmark now report that bioactive TACE is expressed in normal colon mucosa by mononuclear and epithelial cells. However, TACE activity is increased in mucosal biopsies from patients with active ulcerative colitis, raising speculation that TACE might be a new therapeutic target in IBD. Gut (2002) 51, 37–43 SW
Cat allergies treated with peptides A major cat allergen, FEL d1, has been sequenced and characterized. By removing the B-cell epitopes and using overlapping peptides rather than the complete http://immunology.trends.com
antigen, the risks of inducing anaphylaxis in patients is reduced. Initial vaccination with overlapping peptides in single doses were not particularly successful in desensitization. However, multiple doses of these peptides reduce both the early and late phases of allergic skin reactions to FEL d1. This effect was matched with measures of cytokine production by peripheral blood mononuclear cells [interleukin (IL)-10 increased, whereas interferon (IFN)-γ, IL-4 and IL-13 decreased]. The matching of immunological readouts with skin test results will help guide future trials of peptide vaccination. This strategy offers a potentially valuable therapeutic avenue to those allergic patients whose allergen or allergens are identifiable. Lancet (2002) 360, 47–53 CM
Gene linked to asthma risk Researchers have identified a gene that might make some people more susceptible to asthma. A collaboration involving researchers from the USA and UK has discovered a region on chromosome 20 that could be associated with asthma. Certain variations in the gene, termed ADAM33, occur more commonly in people diagnosed with asthma than among those without the disease. The linkage between the gene and asthma increased by a factor of 10 when the researchers only looked at DNA from children who had hyper-responsive airways. The discovery of a single gene that many asthmatic children have in common might teach researchers something about how the disease develops and will hopefully open
new routes for therapeutic targeting. Nature (2002) 418, 426–430 SW
Pathogen infighting Immunocompromised patients become susceptible to invasion by organisms, in particular, fungi. A common clinical challenge is to determine which of these organisms are present and how probable they are to be invasive, a problem made more difficult by interactions between them. Pseudomonas species form a biofilm on Candida albicans filaments, killing the fungus. They do not, however, bind to the yeast form of the fungus, which is invasive and pathogenic in some situations. It is not clear from these early studies whether such Pseudomonas virulence factors help or hinder a patient, or the clinician debating which antimicrobial to use. It is probable, however, that some novel weapons for antifungal defence might well be uncovered in the exploration of this interaction outside host cell walls. Science (2002) 296, 229–232 CM
Prion protection? The need to protect those knowingly exposed to prion agents has not been met. Providing a non-specific stimulus to the
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
These results are important because they provide evidence that IL-2 acts through third-party cells, specifically CD4+CD25+ regulatory cells, to inhibit the survival of CD8+ memory T cells. It will be interesting to see if CD4+CD25+ regulatory cells provide a mechanism for IL-2 to affect the activity of other immune cells, such as activated T cells or even non-T cells. If so, this would
TRENDS in Immunology Vol.23 No.9 September 2002
describe a rational strategy of immune regulation, in which the immune-promoting effects of sustained and high levels of IL-2 are counterbalanced by the inhibitory effects of IL-2-sensitive regulatory T cells. Thus, the results from Murakami et al. provide crucial insight into the mechanisms that might underlie the paradoxical effects of IL-2 on the immune response.
431
1 Murakami, M. et al. (2002) CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc. Natl. Acad. Sci. U. S. A. 99, 8832–8837
Mark P. Rubinstein [email protected] Mark I. Block [email protected]
Respectability for regulatory T cells Like a favorite aunt returning from exotic travels to marry the local vicar, regulatory T (Tr) cells have overcome their former notoriety and entered a new era of respectability. Following the original description of CD4+CD25+ Tr cells, studies of this regulatory subset have been gathering momentum. A recent paper has provided answers to several outstanding questions and offers a new framework within which to think about the differentiation of Tr cells and the generation of tolerance. Apostolou et al. [1] used a murine model in which animals bearing a transgenic T-cell receptor (TCR) specific for an influenza hemagglutinin (HA) peptide were exposed to cells expressing HA under the control of the Igκ promoter. T cells isolated from double transgenics displayed features of Tr cells. They secreted interleukin (IL)-10, expressed high levels of the negative costimulators, CTLA-4 and PD-1, failed to proliferate upon antigen challenge and, most importantly, inhibited the responses
of other T cells with specificity for the same antigen. Interestingly, these Tr cells included both CD25+ or CD25− subsets, which appeared functionally equivalent. The CD25 phenotype of the Tr cell depended on the cells that initially presented the tolerizing HA. Presentation of the antigen on the surface of a thymic epithelial cell resulted primarily in the generation of CD4+CD25+ Tr cells, whereas expression of HA on (unactivated) bone marrow-derived cells resulted predominantly in the generation of CD4+CD25− Tr cells. These experiments also revealed that Tr cells can be generated both intrathymically, by high affinity TCR interactions in the thymic cortex, and extrathymically, from naïve, but functionally mature, T cells. This work closely parallels other studies in which the same antigen was expressed under the control of the SV40 rather than the Igκ promoter. With the SV40 promoter, Tr-cell function strictly segregates with the CD25+ phenotype, lending further support
to the notion that the nature of the cells on which the HA antigen is presented, and/or its expression density, might influence the CD25 phenotype of Tr cells. In neither study is the precise nature of the relevant antigen-presenting cell defined. The mechanism by which T cells are stimulated to differentiate along a regulatory rather than a more conventional helper T-cell path also remains a mystery. However, given the current level of interest in Tr cells, the answers to these and other questions regarding them will soon be found. 1 Apostolou, I. et al. (2002) Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 10.1038/ni816 (http://www.nature.com/ni/)
Judy Owen [email protected] Jennifer Punt [email protected]
Successful skin grafts carry persuasive passengers Therapeutic induction of peripheral tolerance is known to involve at least two phenomena: dominant tolerance, whereby pre-existing regulatory T (Tr) cells disarm non-tolerant naïve cells, and infectious tolerance, whereby novel regulatory cells emerge from the naïve-lymphocyte population. Although it is apparent from many murine studies that the cells mediating dominant tolerance are CD4+, little further characterization of the cells has been performed. In particular, whether the active cells are related to the populations of CD4+CD25+ Tr cells, which are proposed to be the principal exponents of protection against autoimmune disease, has not been explored. Furthermore, it is not known if http://immunology.trends.com
CD4+ regulatory cells circulate through tolerated grafts because they have only been detected thus far in lymphoid tissues. Luis Graca et al. addressed these issues in two recent publications [1,2]. Their first paper examines the functional characteristics of CD4+CD25+/− Tr cells [1]. Dominant tolerance was initiated in CBA strain mice receiving allogeneic (B10.BR strain) skin grafts by treatment with non-depleting monoclonal antibodies to CD4 and CD8 at the time of transplantation. When transferred to ‘empty’ (i.e. thymectomized and T-cell depleted) CBA mice, the CD4+ Tr cells induced by this regimen failed to reject new B10.BR grafts and indeed could
abrogate rejection by co-transferred naïve (i.e. non-tolerant) cells. Both CD4+CD25+ and CD4+CD25− cells had the capacity to mediate dominant tolerance, although CD25+ cells were ~10-times more potent. A clear difference in the phenotype of the two cell populations was further highlighted by serial analysis of gene expression: activated CD4+CD25+ cells expressed ≥103 new transcripts, many of them unique and not yet assigned to known genes. The dominant regulatory cells implicated in this paper were isolated from the spleens of tolerant mice [1]. Graca et al. then used the same grafting model to investigate the presence of these cells within tolerated skin grafts [2].
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
432
News & Comment
The procedure involved an additional step: B10.BR skin that had previously been grafted to, and tolerated by, CBA mice was collected and re-grafted to ‘empty’ CBA mice. After 30 days, a second B10.BR skin graft was applied, with or without concurrent administration of naïve lymphocytes. The original graft was shown to carry ‘passenger’ CD4+CD25+/− Tr cells, which could prevent naïve cell-mediated rejection of the second graft. Additionally, the use of RAG1−/− mice as graft recipients showed that the T cells could expand from the grafted skin to peripheral blood and evoke regulatory function. However, despite the presence of Tr cells peripherally and in lymphoid organs, Zelenika et al.
TRENDS in Immunology Vol.23 No.9 September 2002
found their activity to be concentrated in the graft [3], suggesting that perhaps regulatory cells recirculate through the body, but accumulate and exert clinically evident effects at sites where their target antigens are present. Careful use of control groups established that T-cell regulatory function was not an artifact of the sorting procedure (indeed, unsorted cells showed greater tolerizing potency) [1], tolerant animals were not immunosuppressed and tolerance was not a result of microchimerism but, instead, was entirely reliant on T cells residing within, and then expanding from, the tolerated skin [2]. The role of CD4+CD25+/− Tr cells in mediating
transplantation tolerance will undoubtedly receive much further attention, particularly given the high demand for overcoming organ rejection in clinical settings. 1 Graca, L. et al. (2002) Both CD4+CD25+ and CD4+CD25− regulatory cells mediate dominant transplantation tolerance. J. Immunol. 168, 5558–5567 2 Graca, L. et al. (2002) Identification of regulatory T cells in tolerated allografts. J. Exp. Med. 195, 1641–1646 3 Zelenika, D. et al. (2002) Regulatory T cells overexpress a subset of Th2 gene transcripts. J. Immunol. 168, 1069–1079
Sarah Hudson Keenihan [email protected]
In Brief
A place for TACE in inflammatory bowel disease Tumour necrosis factor (TNF)-α has a central pathogenic role in inflammatory bowel disease (IBD). During local and systemic inflammatory reactions, membrane-bound TNF-α is cleaved extracellularly by a specific zinc metalloprotease, termed TNF-α-converting enzyme (TACE). This yields the soluble form of TNF-α that acts as a compartmentalized or circulating cytokine. It was originally thought that cleaved TNF-α was the major biological active form, but membraneexpressed TNF-α is biologically active. Researchers in Denmark now report that bioactive TACE is expressed in normal colon mucosa by mononuclear and epithelial cells. However, TACE activity is increased in mucosal biopsies from patients with active ulcerative colitis, raising speculation that TACE might be a new therapeutic target in IBD. Gut (2002) 51, 37–43 SW
Cat allergies treated with peptides A major cat allergen, FEL d1, has been sequenced and characterized. By removing the B-cell epitopes and using overlapping peptides rather than the complete http://immunology.trends.com
antigen, the risks of inducing anaphylaxis in patients is reduced. Initial vaccination with overlapping peptides in single doses were not particularly successful in desensitization. However, multiple doses of these peptides reduce both the early and late phases of allergic skin reactions to FEL d1. This effect was matched with measures of cytokine production by peripheral blood mononuclear cells [interleukin (IL)-10 increased, whereas interferon (IFN)-γ, IL-4 and IL-13 decreased]. The matching of immunological readouts with skin test results will help guide future trials of peptide vaccination. This strategy offers a potentially valuable therapeutic avenue to those allergic patients whose allergen or allergens are identifiable. Lancet (2002) 360, 47–53 CM
Gene linked to asthma risk Researchers have identified a gene that might make some people more susceptible to asthma. A collaboration involving researchers from the USA and UK has discovered a region on chromosome 20 that could be associated with asthma. Certain variations in the gene, termed ADAM33, occur more commonly in people diagnosed with asthma than among those without the disease. The linkage between the gene and asthma increased by a factor of 10 when the researchers only looked at DNA from children who had hyper-responsive airways. The discovery of a single gene that many asthmatic children have in common might teach researchers something about how the disease develops and will hopefully open
new routes for therapeutic targeting. Nature (2002) 418, 426–430 SW
Pathogen infighting Immunocompromised patients become susceptible to invasion by organisms, in particular, fungi. A common clinical challenge is to determine which of these organisms are present and how probable they are to be invasive, a problem made more difficult by interactions between them. Pseudomonas species form a biofilm on Candida albicans filaments, killing the fungus. They do not, however, bind to the yeast form of the fungus, which is invasive and pathogenic in some situations. It is not clear from these early studies whether such Pseudomonas virulence factors help or hinder a patient, or the clinician debating which antimicrobial to use. It is probable, however, that some novel weapons for antifungal defence might well be uncovered in the exploration of this interaction outside host cell walls. Science (2002) 296, 229–232 CM
Prion protection? The need to protect those knowingly exposed to prion agents has not been met. Providing a non-specific stimulus to the
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.