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Immune regulation: Driving DC differentiation
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©2004 Nature Publishing Group RESEARCH HIGHLIGHTS NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | SEPTEMBER 2004 | 661 Little is known about the transcrip- tional control of dendritic-cell (DC) differentation, but a study reported in Immunity now shows that the lipid- activated transcription factor peroxi- some proliferative activated receptor-γ (PPARγ) is upregulated early after DC differentiation from monocytes. This might be important to control the ability of DCs to stimulate invariant natural killer T (iNKT) cells, a popula- tion of autoreactive cells that seem to have a role in controlling the development of autoimmune disease. The authors decided to investi- gate the role of PPARγ in DC differ- entiation because it is known to be expressed by both macrophages and DCs, and because PPARγ regulates the expression of CD36 — a surface receptor that mediates uptake of apoptotic cells. In this study, the role of PPARγ was examined using a human monocyte-derived DC sys- tem. PPARγ expression (at both the mRNA and protein levels) was found to be upregulated to a high level within a few hours of DC differentia- tion. Treatment of DCs with a PPARγ- specific agonist induced a phenotypic change in the DCs, including a decrease in the expression of CD1a, an increase in the expression of CD1d and an enhancement of endocytic activity. CD1 molecules are non- classical MHC-class-I-like molecules, and CD1d can present lipid or glyco- lipid antigens to iNKT cells. The results of this study show that CD1 expression during DC differentiation is coordinately regulated by activation of PPARγ, and DCs treated with the PPARγ agonist were able to activate iNKT cells more efficiently in the presence of α-galactosyl ceramide — which is presented by CD1d — than were untreated DCs. What are the biological implica- tions of this study? Reduced numbers of iNKT cells have been associated with the development of autoimmune dis- eases, and it might be possible to mod- ify autoimmune diseases by enhancing CD1d expression and iNKT activation through the targeting of PPARγ. Elaine Bell References and links ORIGINAL RESEARCH PAPER Szatmari, I. et al. Activation of PPARγ specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion. Immunity 21, 95–106 (2004). FURTHER READING Wilson, S. B. & Delovitch, T. L. Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nature Rev. Immunol. 3, 211–222 (2003) | Daynes, R. A. & Jones, D. C. Emerging roles of PPARs in inflammation and immunity. Nature Rev. Immunol. 2, 748–759 (2002). WEB SITE Laszlo Nagy: http://www.hhmi.org/research/ scholars/nagy-l.html Driving DC differentiation IMMUNE REGULATION IN BRIEF Serine protease inhibitor 2A is a protective factor for memory T cell development. Liu, N. et al . Nature Immunol . 15 August 2004 (doi:10.1038/ni1107). The mechanisms by which antigen-specific CD8 + T cells escape programmed cell death (PCD) and become memory cells are not well established. Now, Liu et al. report a crucial protective role for serine protease inhibitor 2A (SPI2A), which inhibits PCD triggered by cathepsins. By screening for candidate genes, the authors showed that SPI2A expression was upregulated by memory T cells but not by naive T cells. Effector T cells from bone-marrow chimeric mice expressing a SPI2A transgene showed suppression of cathepsin B activity and induction of PCD.Accordingly, more virus-specific memory cells survived in these mice following viral infection, indicating that commitment to the memory lineage is facilitated by the upregulation of protective genes. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Allen, C. D. C. et al . Nature Immunol . 1 August 2004 (doi:10.1038/ni1100). This study explores the mechanisms involved in segregating B cells to the dark and light zones of germinal centres (GCs), in which they carry out somatic hypermutation and antigen- driven selection, respectively. By generating fetal-liver chimeras, the authors show that deficiency in the chemokine receptor CXCR4 results in disrupted GC compartmentalization. Immunohistochemical analysis indicated that centroblasts undergoing somatic hypermutation expressed high levels of CXCR4 and localized to the dark zone, which is consistent with higher expression of the CXCR4 ligand CXCL12 in the dark zone compared with the light zone. By contrast, expression of CXCR5 and its ligand CXCL13 were concentrated in the light zone and contributed to recruitment of cells to this zone. Tumour necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. Xanthoulea, S. et al . J. Exp. Med. 200, 367–376 (2004). Although the pro-inflammatory effects of tumour-necrosis factor (TNF) are beneficial to host defence, they can be harmful if not controlled. Proteolytic cleavage (shedding) of cell-surface TNF receptor p55 (TNFRp55) modulates TNF function, and in humans, impaired receptor shedding is linked to a group of autoinflammatory syndromes. In this study, knock-in mice heterozygous or homozygous for a non-sheddable TNFRp55 spontaneously developed TNF-dependent chronic inflammation of the liver and were increased in their susceptibity to TNF and lipopolysaccharide toxicity, as well as chronic inflammatory disease. By contrast, these animals showed increased resistance to infection with Listeria monocytogenes. These effects indicate a crucial role for TNFRp55 shedding in the regulation of the effects of TNF in vivo. INFLAMMATION LYMPHOID ARCHITECTURE T-CELL MEMORY
Transcript of Immune regulation: Driving DC differentiation
© 2004 Nature Publishing Group
R E S E A R C H H I G H L I G H T S
NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | SEPTEMBER 2004 | 661
Little is known about the transcrip-tional control of dendritic-cell (DC)differentation, but a study reported inImmunity now shows that the lipid-activated transcription factor peroxi-some proliferative activated receptor-γ(PPARγ) is upregulated early after DCdifferentiation from monocytes. Thismight be important to control theability of DCs to stimulate invariantnatural killer T (iNKT) cells, a popula-tion of autoreactive cells that seemto have a role in controlling thedevelopment of autoimmune disease.
The authors decided to investi-gate the role of PPARγ in DC differ-entiation because it is known to beexpressed by both macrophages andDCs, and because PPARγ regulates theexpression of CD36 — a surfacereceptor that mediates uptake ofapoptotic cells. In this study, the roleof PPARγ was examined using ahuman monocyte-derived DC sys-tem. PPARγ expression (at both themRNA and protein levels) was foundto be upregulated to a high levelwithin a few hours of DC differentia-tion. Treatment of DCs with a PPARγ-specific agonist induced a phenotypicchange in the DCs, including adecrease in the expression of CD1a,an increase in the expression of CD1dand an enhancement of endocytic
activity. CD1 molecules are non-classical MHC-class-I-like molecules,and CD1d can present lipid or glyco-lipid antigens to iNKT cells. Theresults of this study show that CD1expression during DC differentiationis coordinately regulated by activationof PPARγ, and DCs treated with thePPARγ agonist were able to activateiNKT cells more efficiently in thepresence of α-galactosyl ceramide —which is presented by CD1d — thanwere untreated DCs.
What are the biological implica-tions of this study? Reduced numbersof iNKT cells have been associated withthe development of autoimmune dis-eases, and it might be possible to mod-ify autoimmune diseases by enhancingCD1d expression and iNKT activationthrough the targeting of PPARγ.
Elaine BellReferences and links
ORIGINAL RESEARCH PAPER Szatmari, I. et al.Activation of PPARγ specifies a dendritic cellsubtype capable of enhanced induction of iNKT cell expansion. Immunity 21, 95–106(2004). FURTHER READING Wilson, S. B. & Delovitch, T. L. Janus-like role of regulatory iNKT cells in autoimmune disease and tumourimmunity. Nature Rev. Immunol. 3, 211–222(2003) | Daynes, R. A. & Jones, D. C. Emergingroles of PPARs in inflammation and immunity.Nature Rev. Immunol. 2, 748–759 (2002).WEB SITELaszlo Nagy: http://www.hhmi.org/research/scholars/nagy-l.html
Driving DC differentiation
I M M U N E R E G U L AT I O N IN BRIEF
Serine protease inhibitor 2A is a protective factor formemory T cell development.Liu, N. et al. Nature Immunol. 15 August 2004 (doi:10.1038/ni1107).
The mechanisms by which antigen-specific CD8+ T cells escapeprogrammed cell death (PCD) and become memory cells are notwell established. Now, Liu et al. report a crucial protective role forserine protease inhibitor 2A (SPI2A), which inhibits PCD triggeredby cathepsins. By screening for candidate genes, the authors showedthat SPI2A expression was upregulated by memory T cells but notby naive T cells. Effector T cells from bone-marrow chimeric miceexpressing a SPI2A transgene showed suppression of cathepsin Bactivity and induction of PCD. Accordingly, more virus-specificmemory cells survived in these mice following viral infection,indicating that commitment to the memory lineage is facilitated by the upregulation of protective genes.
Germinal center dark and light zone organization ismediated by CXCR4 and CXCR5.Allen, C. D. C. et al. Nature Immunol. 1 August 2004 (doi:10.1038/ni1100).
This study explores the mechanisms involved in segregating B cells to the dark and light zones of germinal centres (GCs),in which they carry out somatic hypermutation and antigen-driven selection, respectively. By generating fetal-liver chimeras,the authors show that deficiency in the chemokine receptorCXCR4 results in disrupted GC compartmentalization.Immunohistochemical analysis indicated that centroblastsundergoing somatic hypermutation expressed high levels ofCXCR4 and localized to the dark zone, which is consistent withhigher expression of the CXCR4 ligand CXCL12 in the dark zonecompared with the light zone. By contrast, expression of CXCR5and its ligand CXCL13 were concentrated in the light zone andcontributed to recruitment of cells to this zone.
Tumour necrosis factor (TNF) receptor sheddingcontrols thresholds of innate immune activation thatbalance opposing TNF functions in infectious andinflammatory diseases.Xanthoulea, S. et al. J. Exp. Med. 200, 367–376 (2004).
Although the pro-inflammatory effects of tumour-necrosis factor (TNF) are beneficial to host defence, they can be harmful if not controlled. Proteolytic cleavage (shedding) of cell-surfaceTNF receptor p55 (TNFRp55) modulates TNF function, and in humans, impaired receptor shedding is linked to a group ofautoinflammatory syndromes. In this study, knock-in miceheterozygous or homozygous for a non-sheddable TNFRp55spontaneously developed TNF-dependent chronic inflammation of the liver and were increased in their susceptibity to TNF andlipopolysaccharide toxicity, as well as chronic inflammatory disease.By contrast, these animals showed increased resistance to infectionwith Listeria monocytogenes. These effects indicate a crucial role forTNFRp55 shedding in the regulation of the effects of TNF in vivo.
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