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J Immunol 2004; 173:5331-5332; ; doi: 10.4049/jimmunol.173.9.5331 This information is current as http://www.jimmunol.org/content/173/9/5331 of September 29, 2021. Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE

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IL-27 inhibits Th2 immune and living organotypic brain slice cultures treated with a neuro- toxin were protected against neuronal cell death by prior treatment responses with EGCG. However, no accumulation of I␬B-␣ was seen in brain tissue; rather, EGCG prevented the formation of reactive epending on the cytokine oxygen species in neurons treated with an inhibitor of glutathione environment, IL-27, which synthetase. The data demonstrate that EGCG, the major polyphe- is closely related to IL-12, D nolic compound of green tea, has both neuroprotective and anti- interacts with its receptor WSX-1 to inflammatory activities in EAE. promote or inhibit Th1 cell inflammatory responses. However, the role of IL-27/WSX-1 interactions in Th2 cell responses is unknown. Artis et al. (p. 5626) found Regulating IL-13 expression in increased levels of IL-27 mRNA in mesenteric lymph nodes of C57BL/6 mice infected 1 and 2 wk earlier with the gastrointestinal mast cells Ϫ Ϫ Downloaded from helminth parasite Trichuris muris. WSX-1 / mice cleared all lar- lthough GATA-3 is known to stimulate T cell-spe- val parasites by day 14 postinfection and produced higher levels of cific expression of IL-13, factors that induce IL-13 ex- Th2 cytokines (IL-4, IL-5, and IL-13) than infected wild-type A pression in mast cells are not defined. On p. 5564, mice. Mutant mice also demonstrated intestinal goblet cell hyper- Masuda et al. show that several murine mast cell lines produced plasia, increased mucin production, higher numbers of intestinal IL-13 in response to PMA/ionomycin stimulation; one line also

mast cells, and degranulation products. All of these type 2 cyto- responded to stimulation with LPS or by IgE cross-linking. The http://www.jimmunol.org/ kine-dependent responses were significantly reduced in infected Ϫ Ϫ Ϫ Ϫ responsive DNA sequences in the IL-13 promoter were mapped WSX-1 / animals that had received anti-IL-4 mAb. WSX-1 / to nt Ϫ106 to Ϫ94 using deletion mutants in luciferase re- mice had a greater mast cell response in vivo to intradermal DNP porter assays. Mutations within the defined region reduced challenge 24 h after DNP-IgE priming compared with wild-type GATA binding to a faster migrating constitutively appearing controls. T cells from infected wild-type and mutant animals pro- complex as determined by EMSA and reduced AP-1 binding to duced equivalent amounts of IFN-␥ following in vitro challenge a slower migrating complex that appeared after stimulation of 14 days postinfection. Treatment of wild-type mice with anti- Ϫ Ϫ transfected mast cells. Cotransfection of a wild-type IL-13 pro- IL-12 and anti-IFN-␥ mAbs did not promote a WSX-1 / -like moter construct with a dominant negative c-jun mutant re- ϩ by guest on September 29, 2021 response to T. muris infection. CD4 T cells from uninfected duced levels of IL-13 promoter luciferase activity. Transcrip- mutant animals had enhanced proliferative responses and production of the wild-type IL-13 promoter construct in stimulated tion of IL-5 and IL-13 upon secondary stimulation under Th2- cells was increased in a dose-dependent manner by cotransfec- polarizing conditions than wild-type cells. The data demonstrate tion with GATA-1 or GATA-2 expression plasmids. This trans- that IL-27 and WSX-1 interact in an IFN-␥-independent manner activation did not occur with the AP-1 binding site mutant or in to inhibit mucosal Th2 immune responses. the presence of the c-jun mutant. Analyses of IL-13 promoter- binding proteins showed that GATA proteins were constitutive Green tea and EAE in the nuclei but that c-fos and c-jun appeared only after stimulation of the cells; GATA-1 copurified with AP-1. GATA de- xperimental autoimmune encephalomyelitis (EAE) is letion mutants defined three regions of protein interaction with an inflammatory neural disease often studied as an an- c-jun. The results show that AP-1 and GATA cooperate to imal model of human multiple sclerosis. To define an E transactivate the IL-13 gene in mast cells and that AP-1 is in- agent that is neuroprotective in both diseases, Aktas et al. (p. dispensable for this activity. 5794) studied a polyphenol, (Ϫ)-epigallocatechin-3-gallate (EGCG), found in green tea. Treatment of SJL/J mice with 60 ␮g of EGCG twice daily, beginning at the time of immunization with Eliminating autoreactive memory an EAE-inducing protein, resulted in reduced inflammatory le- B cells sions in the brain stem and spinal cord, and lower clinical scores compared with vehicle-treated mice. The proliferative response n their prior studies on nega- and TNF-␣ production of draining lymph node T cells from tive selection of autoreactive B EGCG-treated immunized animals were reduced compared with I cells, Caton and colleagues controls. The in vitro expansion of myelin basic protein-specific found persistence of B cells capable of primary and memory re- ϩ human CD4 T cells in response to peptide-loaded APCs or to sponses in mice (HA104) transgenically expressing an influenza anti-CD3/CD28 activation also was inhibited. EGCG reduced virus protein (PR8 HA) under the control of a viral promoter. expression of cyclin-dependent kinase 4 and blocked proteasome In Guay et al. (p. 5485), the same group developed a strain of activity, resulting in I␬B-␣ accumulation and in inhibition of transgenic mice (HACII) that expressed PR8 HA as a membrane- ϩ NF-␬B activation in CD4 T cells. EGCG-treated EAE mice had bound Ag driven by a MHC class II promoter. Wild-type and fewer apoptotic neurons in brain tissue sections than control mice, transgenic mice were immunized with a virus containing a single

ϩ amino acid change in PR8 HA. PR8 HA-specific IgG, but not work to determine the mechanism by which CD8 T cells kill IgM, Ab-secreting cells were significantly reduced in both HACII S. Typhi-infected PBMCs from human volunteers. Agents that and HA104 mice compared with wild-type controls; all strains induced degranulation of CTL inhibited the lytic activity, reacted with the mutated PR8 HA. One-half of PR8 HA-specific whereas anti-Fas mAb had no effect. Released granzyme B was IgG-secreting B cell hybridomas from wild-type mice, but none detected in cocultures of CTL with S. Typhi-infected cells. Cy- from either transgenic mouse strain, used the V␬C12 variable totoxic activity was blocked by an inhibitor of HLA class I Ag region. IgM-secreting hybridomas from transgenic mice were half processing, but not by an inhibitor of HLA class II Ag process- V␬C4 and half V␬C12 clonotypes. Purified IgGs from all mice ing. S. Typhi-specific CTL killed all S. Typhi-infected B cell had higher reactivities against PR8 HA than a control Ab, and lines whether allogeneic or autologous with regard to HLA class IgMs from all mice had lower reactivities. Mutant virus challenge I alleles, and cytotoxic activity was blocked by mAb to CD3, of animals immunized with the mutant virus induced IgG Ab- CD8, or HLA-class I. The effector cell population was identi- ϩ ϩ Ϫ secreting splenocytes specific for the mutated epitope in HACII fied as CD3 CD8 CD56 T cells by cell sorting. HLA-E ex- mice; only wild-type and HA104 animals also produced PR8 HA- pression intracellularly and on the surface of uninfected or S. specific IgG Ag-secreting cells. SCID mice injected with a mixture Typhi-infected T cells or of macrophages from uninfected vol- of wild-type and HACII splenocytes and primed 1 day later with unteers was up-regulated after 60-min incubation with CTL ef- the mutated virus generated a memory response after challenge fector cells; anti-HLA-E mAbs partially blocked the up-regula- that was specific for the mutated epitope. The data show that B tion. Increased HLA-E surface expression was seen with S. cells, autoreactive for a membrane-bound Ag, are excluded from Downloaded from Typhi-infected B cells incubated with each of several S. Typhi memory formation in a dominant manner. peptides, and the peptide-loaded infected B cells induced increased release of granzyme-B and IFN-␥ from effector cells. ϩ ϩ Ϫ CCL18 and atopic dermatitis The experiments identify a new CD3 CD8 CD56 CTL ef- llergens, including bacte- fector that recognizes human S. Typhi-infected target cells in a

rial products, initiate the nonclassical HLA-E-restricted manner. http://www.jimmunol.org/ A inflammation of atopic dermatitis, although the mechanism by which they act is unknown. Pivarcsi et al. (p. 5810) High affinity HLA class I binding of determined chemokine expression profiles specific for a variety a 14-aa peptide of skin diseases by quantitative real-time PCR analyses and found significant CCL18 up-regulation in human lesional eptides that bind to MHC atopic skin compared with normal skin or lesional skin of other class I molecules average inflammatory skin diseases. Immunohistochemically, CCL18 8–10 aa in length. It is ex-

P by guest on September 29, 2021 was localized in dendritic cells (DCs) evenly dispersed within pected that longer peptides will the dermal layer and clustered in perivascular pockets. In vitro, have lower binding affinity to HLA IFN-␥ and IL-4 stimulated cultured human primary keratino- molecules. Probst-Kepper et al. (p. cytes and dermal fibroblasts to produce high levels of CCL18 5610) obtained a 1.5-Å resolution mRNA. A variety of microbial-derived compounds or CD40L crystal structure of the human induced expression of CCL18 mRNA and protein in mono- MHC class I molecule HLA- cytes; Langerhans-type DCs and interstitial DCs constitutively B*3501 in complex with a 14-aa-long peptide derived from an expressed high levels of CCL18 mRNA and protein. Exposure alternative reading frame of the human M-CSF. The peptide to house dust mite allergens induced CCL18 mRNA expression was anchored to HLA-B*3501 by 3 aa at its N terminus and 2 aa at its C terminus; the central portion looped out between the in skin of atopic dermatitis patients or in single-cell suspensions ␣ from their lesions. A Staphylococcus aureus superantigen also in- two helices of the HLA groove compared with a control 9-aa duced CCL18 expression in skin and in PBMCs isolated from peptide bound to HLA-B*3501. Substitution of alanine for the proline at aa 2 in the 14-mer reduced flexibility of the looped atopic dermatitis patients. NiSO4 patch treatment of nonatopic Ni-sensitized individuals resulted in CCL18 mRNA induction portion, altered the positioning of the peptide within the bind- in skin cells, whereas a chemical irritant did not. The authors ing groove in regions critical for TCR contact, and decreased conclude that CCL18, up-regulated in DCs of atopic patients recognition by a CTL clone specific for the M-CSF peptide. by a variety of allergens, initiates and amplifies atopic skin in- Proline to alanine substitution at both aa 2 and aa 9 had more flammation. drastic consequences, i.e., almost complete loss in flexibility of the looped region, further divergence in position within the A novel CTL subset in typhoid binding groove, and abrogation of recognition by the CTL. The length of the CDR3s of the M-CSF peptide-specific CTL clone vaccinees were 1 and 2 aa longer than CDR3s of TCRs recognizing pep- ϩ ztein and coworkers have shown that CD8 T cells are tides 8–10 aa in length. The analysis shows that the minimum important in the host response to infection with Salmo- requirement for high-affinity MHC binding is proper N- and S nella enterica serovar Typhi (S. Typhi). In the paper on C-terminal anchoring and suggests that CTLs would recognize p. 5852, Salerno-Goncalves et al. followed up on their previous longer peptides in clinical therapies. Summaries written by Dorothy L. Buchhagen, Ph.D.