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DC-NK interactions in tumor therapy
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. Only TIL from the Adv.IL-12 plus anti-4-1BB Ab-treated mice stimulated Ag-specific T cell proliferation in vitro; this activity was lost after DC depletion of the TIL. Combination-treated mice previously given anti-NK or anti-IFN- Ab had fewer DC, and anti-IFN- Ab reduced the enhanced expression of 4-1BB on mature DC seen in tumor bearing mice treated with Adv.IL-12. More i.v. injected fluorescent-labeled hemopoietic stem cells migrated into the tumors and matured into DC in combination-treated mice vs controls. In vitro, DC cocultured with syngeneic tumor cells expressing a 4-1BB ligand secreted more IL-12 than DC cultured with control cells, and addition of IFN- enhanced IL-12 levels. The authors suggest that NK cells, activated by Adv.IL-12, produce IFN- that regulates 4-1BB expression by DC that, in turn, are activated by agonistic anti-4-1BB Abs administered in the combination therapy. T cells regulate DC maturation
Both CD4+CD25+ T cells and the maturation of dendritic cells (DC) have important roles in modulating T cell responses. However, contact-dependent interactions between CD4+CD25+ T cells and DC have not been explored. Misra et al. (p. 4676
) found that autologous DC, matured in vitro in the presence of GM-CSF and IL-4, had significantly reduced levels of costimulatory molecules CD86, CD80, and CD40 when cocultivated with CD4+CD25+ T cells compared with DC cocultured with CD4+CD25− T cells or with DC cultured in medium with or without cytokines. Down-regulation of the costimulatory molecules was lost when the DC and T cells were separated by 0.4 µm membranes. In addition, DC cocultured with CD4+CD25+ T cells had a 3-fold reduction in stimulation of allogeneic T cells and a significant reduction in proliferation compared with the controls. Anti-TGF-
mAb reversed the suppression by a modest 10%. Production of IL-10 from DC cocultured with CD4+CD25+ T cells was increased 2-fold over that seen in DC cocultured with CD4+CD25− T cells. The data show that CD4+CD25− T cells up-regulate, whereas CD4+CD25+ T cells down-regulate, DC maturation and Ag presentation.
Chimerism and autoimmunity
Following up on their previous finding of increased maternal microchimerism in patients with the multisystem autoimmune disease, juvenile dermatomyositis (JDM), Reed et al. (p. 5041
) looked at the HLA genotypes of the mother and child and at the immunologic reactivity of the chimeric cells. Among JDM families, a sensitive PCR-based assay determined that 28 of 33 (85%) patients were chimeric for maternal cells compared with 11 of 48 (23%) of their healthy siblings. All of the healthy siblings either inherited an HLA-DQA1*0501 allele or had HLA-DQA1*0501 chimeric cells. Maternal cells were detected by fluorescent in situ hybridization in PBMCs from 22 of 30 (73%) JDM male patients compared with 12 of 39 (31%) of their healthy brothers and 5 of 29 (17%) unrelated healthy male controls. Maternal cells also were detected in affected muscle tissue in 16 of 20 (80%) JDM children compared with 2 of 10 (20%) unrelated controls. Chimeric cells isolated from JDM patients had increased frequencies of IFN--secreting T cells after stimulation with PBMCs from a variety of sources, but the highest levels of IFN- transcription were seen when JDM cells were used as stimulators. The authors conclude that the presence of the DQA1*0501 allele on the maternal cells facilitates their traffic into the child, and that the reactivity of the maternal cells contributes to JDM.
FLIPping to Th2
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after CD3/CD28 stimulation in vitro than stimulated memory or naive CD4+ T cells from nontransgenic mice. Addition of anti-IL-4 mAb to the cultures before stimulation decreased Th2 cytokine levels and increased IFN- production, whereas addition of IFN- had no effect. Transcription factor AP-1 binding to its DNA consensus sequence was stronger and AP-1 transcription was higher in transgenic cells by day 3 after TCR activation. TCR activation also resulted in phosphorylation of extracellular-regulated kinase, slightly decreased NF-
B binding, less phosphorylation of IB
, higher expression of GATA-3, and lower expression of T-bet in the transgenic cells. In vivo, c-FLIPL-Tg mice had increased serum IgG1 and IgE levels and developed airway inflammation with eosinophil infiltration and mucus overproduction after OVA sensitization and challenge. The data suggest that the Th2 bias is intrinsic to the c-FLIPL-Tg CD4+ T cells and is a result of impaired NF-B activation and up-regulated GATA-3 levels. TLR5 on intestinal mucosa
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Migration patterns of CD8+ T cells
Tissue-specific homing patterns of lymphocytes are important in host reactions to pathogens and transplants, as well as in treatments aimed at resolving infections and eradicating tumors. Masopust et al. (p. 4875
) found viral Ag-specific CD8+ T cells in spleen, lung, liver, small intestine, and other locations in mice infected 7 days earlier with a gut-restricted rotavirus or 9 days earlier with lung-tropic Sendai virus. Widespread dissemination also was seen for memory CD8+ T cells recovered from mice infected 34 and 64 days earlier with Sendai virus; however, there was enrichment of memory cells in lung-draining mediastinal lymph nodes. Local T cell activation in the absence of infection was achieved by adoptive transfer of OVA-reactive cells into transgenic mice that expressed OVA in the small intestine. OVA-reactive CD8+ T cells were found 5 days after transfer in all tissues examined. Virus-specific memory cells transferred into naive recipients migrated to all organs examined except the intestinal lamina propria and had a preference for the organ from which they were isolated. Memory cells from spleen, liver, and lung lacked CD69 and 7 integrin expression, whereas those from intestinal mucosa were CD69+ and 7 integrin+. Spleen, liver, and lung memory cells transferred into naive mice were induced to express high levels of 7 integrin by virus rechallenge. The authors conclude that activated CD8+ T cells undergo widespread migration regardless of the site of Ag encounter.
WSX-1 in Leishmania infections
The structural and functional homologies of the class I cytokine receptor WSX-1 with the IL-12 receptor suggest that WSX-1 plays a role in differentiation of CD4+ Th1 cells. However, Th1 cell development and IFN- production in WSX-1−/− mice vary with the pathogen. Artis et al. (p. 4672
) found that WSX-1−/− mice were highly susceptible to infection with the parasite, Leishmania major, during the first 6 wk postinfection (p.i.) compared with infected wild-type controls, but they eventually controlled parasite replication and resolved their cutaneous lesions. Lymph node cells from both wild-type and WSX-1−/− mice produced high levels of IL-4 by 4 days p.i.; those levels were maintained for at least 2 wk only in the WSX-1−/− mice. By 6 wk p.i., cells from both mice released equivalent levels of Ag-specific IFN-. Lymphocytes from WSX-1−/− mice stimulated with CD3/CD28 in the presence of IL-12 and anti-IL-4 mAb had a 47% increase in CD4+ T cells producing IFN- vs treatment with control Ab. Lymph node cultures from WSX-1−/− mice treated with anti-IL-4 mAb for 4 wk p.i. produced more IFN- and had enhanced IL-12 responses compared with untreated controls; anti-IL-4 mAb-treated animals contained their parasite infections. The data indicate that WSX-1 acts to induce IFN- production early in an infection when IL-4 production is maximal, but it is not necessary in infections lacking a significant IL-4 response.
Phagocytosing apoptotic B cells
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Summaries written by Dorothy L. Buchhagen, Ph.D.
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