The Journal of Immunology, 2006, 176: 2679-2680.
Copyright © 2006 by The American Association of Immunologists
IN THIS ISSUE
Trophoblasts Deactivate Neutrophils
Protection of the fetus is accomplished by preventing a maternal immune reaction aimed at destroying it. Petty et al. have shown that enzymes of the hexose monophosphate shunt (HMS) are translocated from the plasma membrane to the centrosome in neutrophils from pregnant women. In a follow-up to that work, Petty et al. (p. 3205
) demonstrated that the increased amplitude of Ca2+ signaling in in vitro-activated neutrophils from nonpregnant women returned to normal after contact with cultured trophoblasts. High-frequency NAD(P)H oscillations, indicating HMS activation, were seen in solitary-activated neutrophils but not in cells in physical contact with trophoblasts. Neutrophils, labeled with molecules that fluoresced after exposure to reactive oxygen metabolites (ROMs), were dimmed by contact with trophoblasts and had a reduced rate of ROM release. Neutrophils, derived from patients 3 days after Cesarean delivery, had similar reductions in Ca2+ responses, NAD(P)H oscillations and ROM production after binding to placental trophoblasts from the same patients. Activated neutrophils incubated with a fluorescent glucose analog were brighter than unstimulated cells or activated cells in contact with trophoblast cell fragments. ROM-induced DNA damage measured by TUNEL staining did not occur in trophoblasts in contact with activated neutrophils. The authors show trophoblast-mediated contact-dependent deactivation of neutrophils via decreased NAD(P)H, and ROM production is effected through reduced glucose uptake.
T1D Susceptibility Genes
The Danska laboratory and collaborators have shown that differential susceptibility of NOD mice and the closely related nonobese diabetes resistant (NOR) strain to cyclophosphamide (CY)-accelerated type 1 diabetes (T1D) maps in insulin-dependent diabetes (Idd) loci 4, 5, and 9. In Ivakine et al. (p. 2976
), the same laboratory generated four novel recombinant subcongenic mice carrying NOD-derived Idd4 intervals from CY-T1D-susceptible NOR.NOD-Idd4 mice. Two of these strains developed T1D after CY treatment. The Idd4 locus was mapped to a 1.2 to 1.4 Mb region containing 52 predicted genes whose sequences were highly similar in NOD and C57BL/6 mice but were highly divergent from DBA/2J mice from which the NOR sequences were derived. Microarray analyses showed that five IFN response genes within the Idd4 locus were overexpressed in resting or stimulated bone marrow-derived macrophages of one T1D-susceptible vs one resistant strain. Real-time PCR expression analysis of all 52 genes identified seven genes displaying differential expression in macrophages from NOR vs NOR.NOD-Idd4 mice; two of the genes had been identified in the microarray analyses. The authors identify five high priority candidate genes within the Idd4 locus that could influence T1D susceptibility in NOD mice.
TLR7/8 and HIV Infection
Several TLRs are implicated in defenses against ssRNA viruses. Although two of those, TLR7 and TLR8, are triggered by HIV, they are not represented on CD4+ T cells. Schlaepfer et al. (p. 2888
) found that treatment of human aggregate lymphocyte cultures (HLACs) from tonsils or PBMCs with a complex of HIV ssRNA plus a cationic lipid or with the synthetic compound R-848 rendered the cells resistant to HIV infection. The effect was not seen with compounds that triggered other TLRs. The anti-HIV effect was reversed by depleting cultures of B cells or in a T cell line cocultured with a B cell line pretreated with R-848. R-848 conditioned medium from HLACs inhibited HIV replication in a HeLa cell line infected with HIV, whereas R-848 added directly to the virus-producing cells had no effect. mAb neutralization of cytokines stimulated by TLR7/8 triggering did not abrogate the R-848 anti-HIV activity. Cultures treated with R-848 had decreased expression of HIV receptors CD4 plus either CCR5 or CXCR4 and less expression of vesicular stomatitis virus envelope pseudotyped replication-deficient HIVs encoding luciferase. R-848 inhibited viral replication when added to HLACs before or within 4 days of HIV infection. In contrast to the ability of R-848 to prevent acute HIV infection, it induced production of the virus when added to promonocytic cell lines latently infected with HIV. The results indicate that HIV ssRNA or R-848 acts through TLR7/8 on B cells to interfere with acute HIV infection of CD4+ T cells at a point after entry but before viral cDNA integration. R-848 activates latent virus in monocytes.
IL-18 and UV-Induced DNA Damage
Increase in skin cancer in the United States is a result of greater UV-induced DNA damage in keratinocytes. Schwarz and colleagues showed that IL-12 acts via DNA repair enzymes to reduce the amount of DNA damage in vitro and in vivo and to prevent UV-induced immunosuppression; IL-12 also breaks UV-induced immunotolerance. In their follow-up, Schwarz et al. (p. 2896
) found reduced apoptosis in human epidermoid carcinoma cells and normal human keratinocytes treated with IL-18 2 h before irradiation. Immunohistochemistry using an Ab against a specific UV-induced DNA lesion demonstrated less damage in skin from C57BL/6 mice that received IL-18 intracutaneously 3 h before UV exposure than controls. IL-18 did not protect mice deficient in a key DNA repair enzyme against UV-induced DNA damage. The inability of wild-type mice to mount a contact hypersensitivity response to an irritant applied to UV-exposed skin was reversed by i.p. injection of IL-18 3 h before irritant application. However, injection with IL-12, but not IL-18, 3 h before resensitization broke tolerance in UV-tolerized mice. IL-18 had no effect on the lack of response of UV-irradiated mice deficient in the DNA repair enzyme. The authors show that IL-18, like IL-12, uses DNA repair to reduce UV-induced apoptosis and DNA damage in human keratinocytes in vitro and to prevent immunosuppression in UV-exposed mice.
Lupus and Infections
Systemic lupus erythematosus susceptibility is conferred by a combination of polymorphic variants of several genes. Mehrad et al. (p. 3233
) hypothesized that individual polymorphisms benefit the host by conferring resistance to bacterial infections. C57BL/6 (B6) mice congenic for the lupus-associated Sle3 locus (B6.Sle3) had fewer bacteria in lungs and blood and greater alveolar infiltration of neutrophils 2 days after intrapulmonary infection of Klebsiella pneumoniae than wild-type B6 mice or B6 mice congenic for two other lupus-associated loci. Lung CD4+ T cells also were elevated in infected B6.Sle3 mice compared with controls. Lung bacterial burden was reduced greatly in infected irradiated B6 recipients of B6.Sle3 bone marrow vs B6 recipients of B6 bone marrow. A similar reduction of bacteria and greater numbers of i.p. neutrophils were detected in B6.Sle3 mice in a model of intra-abdominal sepsis. Lung levels of neutrophil chemotactic chemokines were equivalent in wild-type and B6.Sle3 mice, but in vitro apoptosis of B6.Sle3 neutrophils exposed to heat-killed K. pneumoniae was lower than that of wild-type neutrophils as measured by annexin V staining and microscopy. Isolated B6.Sle3 neutrophils incubated with LPS expressed low levels of a proapoptotic member of the Bcl-2 family but high levels of two apoptosis inhibitor proteins. B6 mice treated with a pan-caspase inhibitor had more lung neutrophils but less neutrophil apoptosis and fewer K. pneumoniae than controls. The data demonstrate that a lupus susceptibility locus on a B6 background enhances antibacterial defenses by increasing neutrophil numbers at the site of infection.
Autoantigens in T1D
The common MHC class I variant HLA-A*0201 (HLA-A2.1) associates with type 1 diabetes (T1D) in humans. However, it is difficult to assess the role of this molecule in patients. The Serreze laboratory has shown accelerated T1D development in NOD mice transgenically expressing the human HLA-A2.1 H chain. In Takaki et al. (p. 3257
), the same group introduced a human HLA-A2.1-
2-microglobulin/H-2Db mouse construct (HHD) into NOD mice which then were crossed to a NOD strain lacking 2-microglobulin to eliminate expression of murine class I MHC molecules. Splenocytes of the resulting transgenic mice expressed only HLA-A2.1 molecules; the mice expressed CD8+ T cells at low levels and developed T1D by 30 wk of age. T cells from pancreatic islets of the transgenic mice exhibited HLA-A2.1-restricted cytotoxicity against both human and mouse islets in culture. Monkey kidney cells cotransfected with vectors expressing HHD and murine islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) cDNAs stimulated T cells from islets of the transgenic mice to produce IFN-
. ELISPOT assay identified three IGRP peptides presented by HLA-A2.1-expressing APCs that stimulated IFN- production by transgenic islet CD8+ T cells. One of the peptides was identical in murine and human IGRP; the other two differed by 2 aa each. Eight murine islet-infiltrating T cell cultures recognized the immunodominant murine IGRP peptide and three also recognized the human counterpart. The authors propose that IGRP, a target of CD8+ T cells in humanized NOD mice, is important in T1D in humans.
Memory CD8+ T Cell Survival
The TNFR family member, 4-1BB, is important in long-term survival of activated effector CD8+ T cells. However, 4-1BB expression is transient on activated cells in vivo suggesting that another signal may be required for 4-1BB re-expression after Ag has been cleared. Pulle et al. (p. 2739
) induced 4-1BB and CD69 expression on purified wild-type mouse splenic CD8+ T cells and enhanced cell proliferation and viability by a 48-h treatment with IL-15 but not IL-7. IL-15 induction of 4-1BB was prevented by prior treatment of cells with an inhibitor of MAPK p38 or ERK. Central memory CD8+ T cells were generated by IL-15 treatment of T cells carrying an OVA peptide-specific TCR activated in vitro by OVA peptide. The activated cells were maintained in spleens and bone marrow of wild-type, but not in 4-1BB ligand (4-1BBL)-deficient, mice after adoptive transfer, although the rate of division and proportion of divided cells were similar in both hosts. In comparison with wild-type hosts, 4-1BBL-deficient mice demonstrated a substantial reduction in the number of transferred cells and in the number of IFN--producing splenocytes after in vitro challenge with OVA at 3 wk post transfer. Only 4-1BBL-deficient mice had a defect in the proportion of CD8+ memory phenotype T cells in the bone marrow. The data indicate that 4-1BBL is required to maintain 4-1BB+ memory CD8+ T cells induced by IL-15, Ag activation, and p38 and ERK signals.
Summaries written by Dorothy L. Buchhagen, Ph.D.
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