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In This Issue THE JOURNAL OF IMMUNOLOGY IN THIS ISSUE Limiting C damage rather than decreased proliferation after recruitment by measur- ing infiltrating donor cells 6 h after injection. CXCR6 defi- ϩ reventing the forma- ciency did not alter levels of donor CD8 T cells in the blood or tion of the C3 conver- spleen compared with wild-type donor cells. The data support a ϩ P tase reduces damage specific role for CXCR6 in homing of activated donor CD8 T from inflammation following cells to the inflamed liver in graft-vs-host-induced hepatitis. activation of the mammalian C classical pathway. Schisto- soma complement C2 receptor inhibitor trispanning (CRIT) TLR enhancement of diabetes is known to bind C2 and pre- vent its cleavage. Inal et al. (p. 356) found CRIT homologues in ilham rat virus (KRV) infection of BBDR rats results genomic DNA from Trypanosoma, human, rat, and cod by in type 1 diabetes in ϳ25% of the animals. The fre- Southern blotting and PCR. Ab against an extracellular N- K quency is increased to 100% in rats pretreated with terminal peptide enabled detection of CRIT on the surface of the TLR3 agonist poly(I:C). To investigate the role of TLR- Jurkat cells by flow cytometry. CRIT expression in a wide range induced activation of innate immunity in autoimmune diabetes of human tissues and cells was shown using Abs against the induction, Zipris et al. (p. 131) found that pretreatment of N-terminal peptide and other regions of the protein. The bind- BBDR rats with other TLR ligands, including heat-killed bac- ing of biotinylated C2 to filter-immobilized CRIT or of fluo- teria, also enhanced KRV-induced diabetes induction; some li- rescence-labeled C2 to Jurkat cells was abolished by preincuba- gands were effective at low viral doses that were not usually di- tion of the filter or cells with anti-N-terminal peptide Ab; abetogenic. Treatment with poly(I:C) before low-dose virus biotinylated C2 interaction with C4 or C4b was blocked by the infection resulted in higher serum levels of virus-specific Abs same Ab, by CRIT peptides, or by C4 peptides. Anti-CRIT- compared with low-dose virus infection only. Serum levels of ϩ terminal peptide Ab increased C lysis of CRIT human cells IL-12 p40 were increased in KRV-infected BBDR rats, com- sensitized with anti-lymphocyte Abs. Jurkat cells or the CRIT pared with KRV-infected diabetes-resistant WF rats, but not in N-terminal peptide inhibited C1s-mediated cleavage of C2 BBDR rats infected with nondiabetes-inducing viruses or in protein in vitro, but C2 cleavage occurred after incubation of uninfected controls. Expression of IL-12 p40, IP-10, and ␥ Jurkat cells with anti-N-terminal peptide Ab. The authors con- IFN- mRNAs were higher in pancreatic, cervical, and mesen- clude that CRIT, most likely acquired from parasites via hori- teric lymph nodes from KRV-infected BBDR or WF rats com- zontal transmission, binds C2 to prevent C3 convertase forma- pared with uninfected and vaccinia virus-infected controls. The tion and limit inflammation damage to tissues. IP-10 protein level in pancreatic lymph nodes of KRV-infected BBDR rats was higher than in vaccinia virus-infected rats. The authors conclude that TLR activation of the innate immune system before infection with diabetes-inducing KRV increases disease incidence in BBDR rats. CXCR6 and CD8؉ T cell homing ϩ ccumulation of donor CD8 T cells in the liver of a CD28 regulation of T cell survival transplanted host occurs during graft-vs-host disease. A Although the activated cells express high levels of che- D28 costimulation mokine receptor CXCR6, it is not known whether CXCR6 is of TCR-activated T directly involved in T cell recruitment. Sato et al. (p. 277) cells results in ϩ ϩ C found that liver-infiltrating CD8 and CD4 T cells from Bcl-XL up-regulation and in- mice in which GFP replaced one CXCR6 allele had increased creased cell survival. How- liver accumulation and higher receptor mRNA expression un- ever, the mechanism by der inflamed (allogeneic transfer) conditions vs normal (synge- which CD28 acts is un- neic transfer) conditions. Expression of the ligand CXCL16 known. Wu et al. (p. 180) mRNA also was up-regulated in the inflamed liver. Fewer do- found that anti-CD3/anti- ϩ nor CD8 T cells were found in the inflamed liver6hor7days CD28 mAb costimulation after allogeneic transfer of cells from mice carrying GFP knock- reduced activation-induced ϩ Ϫ Ϫ ins at both CXCR6 alleles; no difference in donor CD4 T cell cell death in wild-type mouse T cells but not in CD28 / T ϩ numbers or percentages was seen. These CD8 T cell reduc- cells or in T cells from transgenic mice carrying a CD28 muta- tions were found to be due to reduced recruitment to the liver tion unable to recruit PI3K. Flowcytometry showed thatBcl-XL Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 2 IN THIS ISSUE protein levels, but not Bcl-2 protein levels, were increased in CTLA-4 and food allergies wild-type cells even in the presenceof anti-IL2 mAb; inhibitors of either PI3K or target of rapamycin (mTOR) kinase activity lthough incidence of food allergies, especially to pea- nuts, is increasing, mechanisms inducing sensitization reduced the costimulation-induced Bcl-XL protein expression. Either anti-CD3 mAb or anti-CD3/anti-CD28 mAbs stimu- are not known. Several lines of evidence suggest that Ϫ Ϫ A / CTLA-4 signaling has a role in tolerance induction. van Wijk et lated Bcl-XL mRNA levels equally in wild-type and CD28 mice. Costimulation also inactivated the repressor of cap-de- al. (p. 174) orally exposed mice to peanut protein extract (PPE) pendent translation. Primary mouse T cells and an established with or without the mucosal adjuvant cholera toxin (CT) in a human T cell line transfected with a luciferase reporter gene un- mouse model of peanut sensitization. Mice treated with PPE Ј plus CT had PPE-specific serum IgG1, IgG2, and IgE, whereas der control of Bcl-XL 5 untranslated nucleotides exhibited en- hanced luciferase activity after costimulation. Luciferase activ- mice treated with PPE alone had only low levels of PPE-specific ity was abolished by cotransfection with a vector expressing a IgG1 and IgG2; IgE was reactive with peanut allergens Arah1, negative regulator of protein synthesis downstream of mTOR Arah3, and Arah6. Anti-CTLA-4 Ab administered during oral sensitization enhanced the PPE-specific Ab levels in the or an antagonist of PI3K. Bcl-XL mRNAs in costimulated wild- type cells were found in the polyribosome pool, whereas those group receiving PPE plus CT but not in the group receiving Ϫ Ϫ in costimulated CD28 / cells were distributed equally be- PPE only. Anti-CTLA-4 Ab treatment increased total IgE levels tween the free and polyribosome pools. The authors conclude in both PPE-exposed groups. Serum levels of mast cell degran- that anti-CD28 costimulation of activated T cells prevents apo- ulation products were elevated only in PPE-challenged mice sensitized with PPE plus CT; anti-CTLA-4 Ab exacerbated the ptosis by relieving inhibition of Bcl-XL mRNA translation through activation of the PI3K/mTOR pathway. response. In vitro treatment with anti-CTLA-4 Ab of mesen- teric lymph node and spleen cells isolated from animals 4 wk after PPE treatment resulted in release of higher levels of IL-4, IL-5, and IL-10; there was no difference between cells cultured with or without PPE. In contrast, elevation of IFN-␥ occurred Plasmacytoid dendritic cell in all anti-CTLA-4 Ab-treated groups, but was significantly in- creased in cells from animals treated with PPE plus CT. The migration authors conclude that CTLA-4 signaling is not the crucial fac- lasmacytoid dendritic cells tor in preventing sensitization to food proteins but regulates the (pDCs) migrate from blood intensity of the allergic response. P to sites of inflammation. Yet, unlike myeloid DCs (mDCs), they do not respond to inflamma- tory chemokines. To identify a che- Preventing burn wound infection mokine receptor and its ligand spe- cific to pDCs, Zabel et al. (p. 244) ne approach to pre- developed a mAb to a human can- venting opportu- didate receptor chemokine-like re- O nistic infections, ceptor 1 (CMKLR1) expressed by and associated mortality, in DCs generated in vitro from mono- severe burn injury patients is cytes. The mAb reacted with a sub- to stimulate production of set of circulating DCs with morphology similar to pDCs but new immune cells. In a not with circulating T cells, B cells, NK cells, or mDCs. CpG mouse model of Pseudomo- oligonucleotide activation of pDCs resulted in down-regula- nas aeruginosa burn wound infection, Toliver-Kinsky et al. (p. 404) found 86% mortality in animals inoculated with bacteria tion of CMKLR expression. Chemotaxis of CMKLR1-trans- immediately after injury. Mortality was reduced to 10% in mice fected cells in response to human serum fractions led to the that had received the hemopoietic cytokine Fms-like tyrosine identification of the protein product of the tazarotene-induced kinase-3 ligand (Flt3L) daily for 5 days before injury and infec- gene 2, or chemerin, as the chemotactic agent. A variety of tis- tion. By 48 h after burn wound inoculation, Flt3L-treated mice sues and organs, most notably liver, pancreas, and adrenal had lower bacterial counts within the wound compared with gland, expressed chemerin mRNA. Serum had more chemerin mice receiving a control injection. Survival was 95% in mice attractant activity than plasma. Recombinant chemerin in- that received i.p.
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