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J Immunol 2004; 173:3579-3580; ; doi: 10.4049/jimmunol.173.6.3579 This information is current as http://www.jimmunol.org/content/173/6/3579 of September 26, 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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Immune response to SARS and induced release of IL-2 from mouse cells expressing the mouse CEACAM1 protein. Human CEACAM1-positive NK clones coronavirus infection in mice were unable to kill human cells expressing CEACAM1 or express- he infectious agent of ing CEACAM6 with both the amino acid R43 and amino acid severe acute respiratory Q44 substitutions. The data show that amino acid R43 and amino T syndrome (SARS) in acid Q44 in the N terminus of CEACAM1 expressed on tumor humans is a novel coronavirus cells protects them against NK cell killing. (SARS-CoV) that also infects a variety of animals including mice. Glass et al. (p. 4030) noted that Immunosuppression induced by virus accumulated at peak levels in the epithelial lining of bronchi and terminal bronchioles in lungs of C57BL/6 (B6) mice infected tryptophan catabolism intranasally 3 days earlier with a clinical isolate of SARS-CoV. In- DO, an enzyme of tryptophan catabolism expressed in IFN- fections were resolved by day 9 postinfection (p.i.), and the animals ␥-activated tolerogenic dendritic cells (DCs), induces immu- Downloaded from had no clinical signs of disease except slower weight gain than I nosuppression. The only ligand known to affect IDO expres- mock-infected controls. Kinetics of virus replication and clearance sion in DCs is CTLA-4. Fallarino et al. (p. 3748) found that all were nearly identical in wild-type B6 mice, in B6 mice lacking NK Ϫ/Ϫ types of mouse DCs, particularly plasmacytoid DCs, bound solu- cells or in CD1 B6 animals lacking NK-T cells. SARS-CoV ble CD200-Ig, a fusion protein of Ig and a widely distributed cell gene and viral RNA expression were detected in lungs of infected Ϫ/Ϫ surface glycoprotein, CD200. CD200-Ig did not modify the sup- ϩ Ϫ http://www.jimmunol.org/ RAG1 mice through day 6 p.i., although no infectious virus pressive activity of untreated CD8 DCs for CD8 DCs loaded was recovered. Epithelial damage similar to that seen in lungs from in- Ϫ Ϫ with a nonapeptide that acted as a mimotope for autoimmune di- / Ϫ fected wild-type mice was noted in lungs of all except the RAG1 abetes in mice. However, CD200-Ig treatment of CD8 DCs or mice. Increased expression of mRNA and protein for a number of in- plasmacytoid DCs caused suppression of T cell-mediated footpad flammatory chemokines and their receptors was detected in lungs Ϫ Ϫ Ϫ swelling induced by the peptide-loaded CD8 DCs; suppression / Ϫ from virus-infected wild-type, NK cell-deficient, and RAG1 B6 by the plasmacytoid DCs, but not by the CD8 DCs, was lost mice. SARS-CoV RNA also was detected by RT-PCR in brain, heart, with the addition of an IDO inhibitor. IDO protein expression in ϩ ϩ liver, and spleen, but not in kidney, of B6 animals through day 9 p.i. CD11c B220 DCs exposed to CD200-Ig alone was enhanced without obvious histological changes; live virus was isolated from brain by coexposure to CpG. Coexposure to CD200-Ig and CpG in- by guest on September 26, 2021 on days 9–15 p.i. and was found predominantly in the hippocampus. duced IFN-␣ production, whereas CD200-Ig alone had no effect. The data suggest that the mouse model of SARS-CoV, in which viral Ϫ/Ϫ Purified plasmacytoid DCs from IFN-␣␤R mice did not pro- clearance does not require NK cells, NK-T cells, or T and B cells, duce IDO protein in response to treatment with the combination might mimic a subclinical human infection. of CD200-Ig and CpG and did not convert tryptophan to kynure- nine. The authors have identified CD200-CD200R interactions on a Molecular basis for inhibition of NK variety of DC subtypes and show that those interactions result in an IDO-dependent tolerance mechanism mediated by type I IFNs. cells by carcinoembryonic Ag proteins embers of the human carcinoembryonic Ag (CEA) Histone deacetylase modulation of Ig-superfamily (CEACAM) interact with each TNF gene expression M other to modulate innate and adaptive immune re- sponses. The Mandelboim group showed that CEACAM1 ho- ranscriptional activation mophilic interactions inhibit NK cell lysis of melanoma cells. of kinase signaling path- Others have shown that CEACAM6 replaces CEACAM1 on T way members regulates some colorectal tumors. In a follow-up to their melanoma inflammatory gene expression in study, Markel et al. (p. 3732) demonstrated binding of a fusion LPS-stimulated monocytes. His- protein, CEACAM1-Ig, to CEACAM1 expressed from a vector tone deacetylases (HDACs) are transfected into human cells; the fusion protein did not bind thought to influence transcrip- to cells expressing CEACAM6. Murine cells expressing a tional activity by modifying the CEACAM1 protein containing mouse sequences released IL-2 acetylation of several DNA-associ- when incubated with irradiated human cells expressing ated proteins. Mahlknecht et al. CEACAM1, but not when incubated with cells expressing (p. 3979) identified recombinant CEACAM6. Replacement of amino acid R43 and amino acid human HDAC3 interaction with Q44 in the N terminus of CEACAM1 with amino acid S43 and MAPK11 on high-density protein amino acid L44 found in CEACAM6, respectively, abolished expression filter membranes and with in vitro-translated MAPK11; homophilic binding with CEACAM1-Ig. The reciprocal sub- HDAC3 coimmunoprecipitated with MAPK11 from lysates of cul- stitution in CEACAM6 conferred strong binding of CEACAM1-Ig tured cells and primary macrophages. Cotransfection of HDAC3 and

MAPK11 cDNA constructs into mammalian cells resulted in acti- absence of Notch1 signaling directs them along the B cell path- vated expression of a reporter construct in a two-hybrid assay, but way. Ho¨flinger et al. (p. 3935) found that pro-B cells from mice truncation of the HDAC3 N terminus eliminated the activity. deficient for the Pax5 B-lineage commitment factor, cultured Transient transfection of promonocytic human cells with the with bone marrow-derived stromal cells ectopically expressing HDAC3-expressing vector inhibited LPS-induced phosphoryla- the Notch ligand Delta-like1 (OP9-DL1), expressed a high tion of MAPK11 and of activating transcription factor 2 (ATF-2) level of Notch1R mRNA compared with normal stromal cells. ϩ ϩ Ϫ Ϫ and reduced the amount of endogenous MAPK11/HDAC3 inter- Single c-Kit B220 Pax5 / pro-B cells cultured with OP9- acting complexes. Other transient transfection experiments DL1 cells in the presence of IL-7 and Flt3 ligand (Flt3L) devel- showed that HDAC3 over-expression inhibited MAPK11-medi- oped into double-positive T cells (59%) which coexpressed ϩ ated ATF-2 activation; small double-stranded inhibitory HDAC3 TCR␤ on the surface (55%); TCR␥␦ cells also were generated RNA reversed transcriptional repression of ATF-2 by HDAC3 (11%). No T cell differentiation was seen in cocultures with and increased NF-␬B activation. Transient transfection of cells Ϫ ϩ control OP9 cells. T cell differentiation to the CD44 CD25 with an HDAC3 expressing vector eliminated both a LPS-induced ϩ stage was seen for KitlowB220 pro-B cells isolated from increase in ATF-2 association with TNF promoter sequences and Ϫ Ϫ Pax5 / bone marrow and cultured with IL-7, Flt3L, and TNF promoter activity and decreased TNF mRNA levels. The Ϫ Ϫ Ϫ Ϫ OP9-DL1 cells; similarly treated Notch1 / Pax5 / pro-B data suggest a model in which HDAC3 controls expression of the Ϫ/Ϫ proinflammatory cytokine TNF by repressing MAPK11/ATF-2 cells failed to develop into T lineage cells. Pax5 bone mar- signaling. row pro-B cells cocultured with OP9-DL1 cells, IL-7 and Flt3L

had increased Thy1.2, c-Kit, and CD25 expression and TCR␥, Downloaded from ␦, and ␤ gene rearrangements; B cell-specific gene expression NO, mitochondria, and calcium was reduced. Expression of several early T cell-specific genes Ϫ Ϫ Ϫ Ϫ was induced in Pax5 / pro-B cells, but not in Notch1 / signaling in lupus T cells Ϫ Ϫ Pax5 / pro-B cells, cultured with OP9-DL1 cells. The au- Ϫ Ϫ nflammation and tissue thors conclude that in vitro T cell development of the Pax5 /

damage in systemic lupus pro-B cells is dependent on Notch1R signaling. http://www.jimmunol.org/ I erythematosus (SLE) patients are induced by abnormally activated, necrotic T cells. NO mediates CD3/CD28 costimu- Dendritic cell priming of NK cells lation-induced mitochondrial endritic cell (DC) ac- hyperpolarization (MHP), pro- tivation of NK cells duction of reactive oxygen inter- is a critical step in 2ϩ D mediates (ROI), and Ca flux-

host defense. NK cells express by guest on September 26, 2021 ing in normal T cells. However, IL-15R, and IL-15 is known to the role of NO in SLE has not been determined. Nagy et al. (p. 2ϩ support NK cell survival and 3676) found that cytosolic and mitochondrial Ca concentra- proliferation. Yet a role for tions were higher in unstimulated and CD3/CD28-activated T IL-15 in DC/NK interactions cells from lupus patients compared with normal controls. NO pro- has not been established. Koka duction in lupus T cells increased to 24 h poststimulation but be- et al. (p. 3594) detected ele- gan to decline in normal T cells at 4 h. A population of T cells with 2ϩ vated expression of IL-12 and MHP, NO production, and increased Ca levels seen at4hinacti- IL-15R␣, a subunit of the IL- vated normal T cells was absent in activated lupus T cells. However, 15R complex, in LPS-stimu- only lupus T cells had an early (2 min) and sustained surge in cytosolic ϩ lated bone marrow-derived DCs (BMDCs) from wild-type Ca2 concentration. Mitochondria in lupus PBLs were increased in mice. However, there were no differences between the ability of numbers per cell and in size compared with mitochondria in normal Ϫ Ϫ wild-type and IL-15R␣ / BMDCs to differentiate into my- PBLs. Although lupus T cells produced more NO than normal T cells, lupus monocytes produced twice as much NO as normal monocytes. eloid DCs and release IL-12 and IL-15. Survival of splenic NK 2ϩ cells required coculturing with BMDCs (expressing or lacking Mitochondrial transmembrane potential and cytosolic Ca concen- ␣ ␥ trations were increased in normal monocyte-depleted PBLs incubated IL-15R ). Activation of NK cells to produce IFN- was in- ␣ with lupus monocytes or with NO alone. Preincubation of normal T duced by LPS-stimulated BMDCs expressing IL-15R , but not ␣Ϫ/Ϫ Ϫ/Ϫ cells with NO also induced MHP, increased mitochondrial mass, and by LPS-stimulated IL-15R or IL-15 BMDCs; anti-IL- ϩ rapid Ca2 fluxing following activation. The authors propose that in- 15R␣, anti-IL-12, and anti-IL-2R␤, but not anti-IL-2R␣, Abs tercellular NO signaling between monocytes and T cells results in per- inhibited the IFN-␥ release. IL-15R␣ expression on BMDCs ϩ sistent MHP and altered Ca2 fluxing in SLE. also was required to prime NK cell cytolytic activity; anti-IL- 15R␣ or anti-IL-2R␤, but not anti-IL-12, Abs blocked the Notch1-dependent T cell priming activity. The ability of IL-15R␣-expressing BMDCs to stimulate IFN-␥ production from NK cells lacking IL-15R␣ development in vitro was prevented by anti-IL-15R␣ Ab. NK cell activation was in- he fate of most immature lymphoid progenitors is decreased in the presence of IL-15 bound to IL-15R␣ attached to termined by signals they receive through contact with culture plates and soluble IL-12. The data provide evidence that T thymic epithelial cells. Exposure to Notch ligands di- murine NK cells are activated by trans presentation of IL-15 by rects the cells along the T cell pathway of development, whereas IL-15R␣ expressed on the surface of DCs. Summaries written by Dorothy L. Buchhagen, Ph.D.