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J Immunol 2010; 184:5421-5422; ; doi: 10.4049/jimmunol.1090029 This information is current as http://www.jimmunol.org/content/184/10/5421 of September 26, 2021. Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/05/03/184.10.5421.DC1 Material

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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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. CD8 Relocates for Expression MK2 in all cell types evaluated. These data reveal cell-type specific roles for TRIF in regulating TNF-a biosynthesis. uring interphase, each D exists in ISGlylating Virulence an uncondensed form in a defined space within the ype 1 IFNs play an important role in cellular re- nucleus called its chromosomal sistance to influenza A virus (IAV) infection by in- cis T territory (CT). Because -regu- ducing the expression of endogenous factors with latory elements are often located antiviral activities. One IFN-stimulated (ISG) is the large distances from their target homolog ISG15, which directly regulates the activity , and/or the transcriptional of target through its conjugation (ISGylation) to machinery is restricted to defined regions within the cell nu- specific lysine residues. In this issue, Tang et al. (p. 5777) cleus, a gene may have to “loop out” from its sub-CT (sCT) to demonstrate that ISG15 attenuates IAV activity via ISGylation achieve the necessary physical interactions required for tran- of the IAV virulence factor nonstructural 1 (NS1). Downloaded from scription. To determine if the CD8 gene locus must undergo Initial experiments revealed that NS1 interacted with the type 1 positional changes to be expressed, Ktistaki et al. (p. 5686) used IFN-inducible ISG15 E3 ligase Herc5. Both IFN-b treatment three-dimensional techniques to asses its relative position to its and virus infection induced Herc5-mediated ISGlyation of sCT and regulatory elements while silenced or actively tran- IAV-NS1, which disrupted its interactions with protein tar- scribed. During thymocyte development, the CD8a gene locus 2 2 gets. ISGlyation also inhibited IAV-NS1 homodimerization, localized within its sCT boundary in CD4 CD8 double- thereby impairing its ability to interact with RNA targets, and http://www.jimmunol.org/ negative and CD4 single-positive (SP) thymocytes, whereas 1 1 was correlated with decreased viral gene induction. Herc5- the CD8a locus had moved out of its sCT in CD4 CD8 mediated ISGlyation of IAV-NS1 derived from the H1N1 double-positive and CD8 SP populations. Likewise, in mature strain A/PR8/34 generated two forms of ISGylated IAV-NS1 lymphocyte populations, the CD8a gene was found within its via the modification of two sets of lysine residues. Markedly, sCT for nonexpressing B cells and CD4 SP cells but had dis- more virulent H5N1 IAV strains displayed only one IS- cernibly repositioned itself outside of the sCT within CD8 Glyated form of NS1. These data support previous reports SP cells. The greater CD8a/b gene locus was also found to that mice deficient in ISG15 exhibit increased susceptibility to cis be clustered spatially with -regulatory elements in CD8- IAV infection. by guest on September 26, 2021 expressing cells. This work reveals a correlation between the spatial organization of the CD8 gene locus relative to its sCT Lymphocyte Longevity and its expression status. n healthy individuals, the ex- 1 Cell-Specific TNF-a Production I pression of CD57 on CD8 T cells correlates with a shorter lifespan and lower numbers oth TLR3 and TLR4 stimulation induce dendritic cells 1 2 and macrophages to release the proinflammatory cy- compared with CD8 CD57 B T cells. Previous studies have sug- tokine TNF-a. Normal levels of TNF-a production gested that the lowered life span for require signaling through the adaptor protein TRIF. In this 1 2 issue, Gais et al. (p. 5842) investigated the mechanism(s) by CD8 CD57 T cells results from which TRIF controls TNF-a biosynthesis. In response to TLR4 an increased rate of apoptosis. In Apoptosis stimulation, TRIF signaling was required for the efficient this issue, Wood et al. (p. 5582) translation of TNF-a mRNA but dispensable for TNF-a investigated a possible correlation between the heat shock pro- mRNA transcription and mRNA stability in both bone marrow tein (Hsp) 27, previously shown to exhibit antiapoptotic ac- tivity, and the disparate life spans of these T cell subsets. When (BM)-derived dendritic cells and BM-derived macrophages. By 1 2 baseline expression levels of in CD57 and CD57 contrast, TRIF signaling was necessary for efficient TNF-a 1 CD8 T cells of normal human donors were compared, Hsp27 mRNA induction when peritoneal macrophages were stimu- 1 1 levels were consistently lower in CD8 CD57 T cells. After 48 h lated with TLR4. Moreover, in response to TLR3 stimulation, z 1 1 a in culture, 50% of CD8 CD57 T cells were undergoing TNF- mRNA production by BM-derived macrophages also z 1 2 required TRIF. Despite these differences, TRIF-mediated apoptosis compared with only 10% of CD8 CD57 T cells. control of TNF-a protein expression was linked to the pro- For both subsets, Hsp27 levels were highest in freshly harvested longed activation of p38 MAPK and the p38 effector kinase cells and decreased significantly as the cells underwent apoptosis. This suggested that the initially lower levels of Hsp27 expression 1 1 in CD8 CD57 cells enhanced their susceptibility to apoptosis. 1 1 Correspondingly, overexpression of Hsp27 in CD8 CD57 Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 cells reduced apoptosis, whereas Hsp27 depletion from www.jimmunol.org/cgi/doi/10.4049/jimmunol.1090029 5422 IN THIS ISSUE

1 2 CD8 CD57 cells increased their rate of apoptosis. Finally, the jection was not enhanced by increased IL-17 levels. These antiapoptotic effect of Hsp27 was linked to its inhibition of studies reveal that NKT cell-derived IFN-g promotes the re- caspase-3 activity. These data define a link between Hsp27 ex- jection of skin grafts by enhancing the primary response of 1 1 1 pression levels and the survival rate of CD8 CD57 T cells. skin-derived Ag-specific CD8 T cells.

Rehabilitating Kupffer Cells Culled by Cathepsin B he pattern recognition receptor TLR9 recognizes upffer cells (KCs) unmethylated DNA containing CpG motifs and is are liver-specific T K expressed on various cell types that include early he- macrophages that matopoietic cells, B cells, and APCs. Stimulation of TLR9 on are important players in common lymphoid progenitors is known to inhibit their dif- normal liver function but ferentiation along the B cell lineage while promoting their have also been negatively differentiation into dendritic cells. To elucidate the effects of implicated in destructive in- TLR9 signaling on B cell-committed lymphopoiesis, Lalanne flammatory responses, such et al. (p. 5678) studied the effects of CpG DNA treatment on as hepatic ischemia/reper- purifiedadultmousepro-andpre-Bcells.Inculture,theaddition fusion (I/R) injury. Ellet et al. (p. 5849) report in this issue that of CpG DNA strongly inhibited IL-7–induced proliferation when I/R is combined with bowel congestion, KCs are actually Downloaded from of pro-B cells but not pre-B cells. Inhibition was due to in- protective. To investigate the role of KC in hepatic injury, creased cell death directly caused by TLR9-mediated signaling murine livers were depleted of KC (.98%) by injection of rather than TLR9-induced soluble factors, such as type I IFN. liposomal clodronate (LC) 48 h prior to ischemia induction. These results were confirmed in vivo by exploring the effects of Following I/R, LC-treated mice had decreased survival CpG/TLR9 signaling in a mouse model that exhibited defective (z55%) compared with diluent-treated control mice (z95%). B cell lymphopoeisis. Finally, TLR9-induced pro-B cell death In the absence of I/R, serum alanine aminotransferase levels http://www.jimmunol.org/ was caspase independent and induced by the release of the ly- were unaffected by LC treatment, but they substantially in- sosomal cysteine protease cathepsin B into the cytosol. These creased in LC-pretreated animals following I/R compared with data define a negative regulatory role for CpG/TLR9-mediated controls. Furthermore, confluent zones of necrosis around signaling during B cell development at the pro-B cell stage that pericentral regions in the liver were found in LC-treated mice is mediated by the activity of cathepsin B. subjected to I/R. Liver sinusoidal endothelial cell activation was found to be substantially increased in LC-treated mice. This Combat-Ready Double Negatives was due to the loss of KC-derived IL-10, as the pretreatment of

LC-treated mice with IL-10 resulted in decreased endothelial or many types of respiratory by guest on September 26, 2021 cell activation and increased survival rates post I/R treatment. F pathogens, such as the Thus, by releasing IL-10, KCs promote survival after hepatic intracellular bacteria Franci- I/R with bowel congestion. These findings have implications sella tularensis, respiratory vaccina- for the treatment of I/R-induced hepatic injuries. tion invokes a superior protection against infection than that provided NKT Cells Prime with IFN-g by traditional parenteral vaccina- tion. To gain insights into the bi- D1d-restricted NKT cells are important players in the ological basis of these differences, C inflammatory immune response. To investigate NKT Cowley et al. (p. 5791) investigated the differential responses cell function during graft rejection, Mattarollo et al. of mice to intranasal (i.n.) and intradermal (i.d.) vacci- (p. 5663) used the K5mOVA transgenic mouse, in which ep- nations with the F. tularensis live vaccine strain (LVS). In- ithelial keratinocytes express OVA, as a skin graft model. When terestingly, double-negative (DN) ab Tcellswerefound K5mOVA skin was grafted onto NKT cell-deficient recipients to effectively respond to sublethal i.d. F. tularensisinfection, initial graft rejection was significantly delayed compared with but they constituted only a minor population of splenic wild-type (wt) recipients. The transfer of in vitro-activated and lung T cells. In contrast, similar numbers of DN T cells 1 1 OVA-specific CD8 T cells into NKT cell-deficient graft re- and CD8 T cells were recruited to the lungs in response cipients overcame the delayed effect. Decreased numbers of to i.n. LVS infection. During the acute phase of the in- 1 OVA-specific, IFN-g–producing CD8 T cells were found in fection, pulmonary DN T cells produced copious amounts NKT cell-deficient graft recipients compared with wt mice. of IFN-g and significantly higher levels of IL-17A than ei- 1 1 However, a second graft evoked similar kinetics in both NKT- ther CD4 or CD8 T cells on day 7 postinfection. Fur- 1 deficient and wt mice, indicating that the memory CD8 T cell thermore, IL-17A–deficient mice exhibited greater response was NKT independent. Grafted wt mice exhibited an susceptiblity to i.n. than i.d. LVS infection. These data show increased ratio of IFN-g to IL-17 production compared with an important role for DN T cell-derived IL-17A in the NKT-deficient mice in draining lymph nodes. When NKT- pulmonary response to LVS infection, thereby establishing 1 1 deficient graft recipients were reconstituted with IFN-g / that i.n. and i.d. vaccinations evoke disparate immune re- NKT cells, they exhibited faster graft rejection than those re- sponses. These observations could lead to improved vaccine constituted with IFN-gKO NKT cells. In contrast, graft re- efficacy for respiratory pathogens. Summaries written by Meredith G. Safford, Ph.D.