Ryotaro Ishimitsu

Overexpression of IL-15 In Vivo Increases Antigen-Driven Memory CD8+ T Cells Following a Microbe Exposure

To elucidate potential roles of IL-15 in the maintenance of memory CD8+ T cells, we followed the fate of Ag-specific CD8+ T cells directly visualized with MHC class I tetramers coupled with listeriolysin O (LLO)91–99 in IL-15 transgenic (Tg) mice after Listeria monocytogenes infection. The numbers of LLO91–99-positive memory CD8+ T cells were significantly higher at 3 and 6 wk after infection than those in non-Tg mice. The LLO91–99-positive CD8+ T cells produced IFN-γ in response to LLO91–99, and an adoptive transfer of CD8+ T cells from IL-15 Tg mice infected with L. monocytogenes conferred a higher level of resistance against L. monocytogenes in normal mice. The CD44+CD8+ T cells from infected IL-15 Tg mice expressed the higher level of Bcl-2. Transferred CD44+CD8+ T cells divided more vigorously in naive IL-15 Tg mice than in non-Tg mice. These results suggest that IL-15 plays an important role in long-term maintenance of Ag-specific memory CD8+ T cells following microbial exposure via promotion of cell survival and homeostatic proliferation.

Overexpression of IL-15 In Vivo Enhances Tc1 Response, Which Inhibits Allergic Inflammation in a Murine Model of Asthma

IL-15, a pleiotropic cytokine, is involved in the inflammatory responses in various infectious and autoimmune diseases. We have recently constructed IL-15-transgenic (Tg) mice, which have an increased number of memory-type CD8+ T cells in the peripheral lymphoid tissues. In the present study, we found that eosinophilia and Th2-type cytokine production in the airway were severely attenuated in OVA-sensitized IL-15-Tg mice following OVA inhalation. IL-15-Tg mice preferentially developed Tc1 responses mediated by CD8+ T cells after OVA sensitization, and in vivo depletion of CD8+ T cells by anti-CD8 mAb aggravated the allergic airway inflammation in IL-15-Tg mice following OVA inhalation. Adoptive transfer of CD8+ T cells from OVA-sensitized IL-15-Tg mice into normal mice before OVA sensitization suppressed Th2 response to OVA in the normal mice. These results suggest that overexpression of IL-15 in vivo suppresses Th2-mediated-allergic airway response via induction of CD8+ T cell-mediated Tc1 response.

Memory phenotype CD8(+) T cells in IL-15 transgenic mice are involved in early protection against a primary infection with Listeria monocytogenes.

We recently constructed IL‐15 transgenic (Tg) mice using cDNA encoding a secretable isoform of the IL‐15 precursor protein under the control of an MHC class I promoter. The IL‐15 Tg mice exhibited resistance against a primary infection with Listeria monocytogenes. The numbers of memory CD8+ T cells were markedly increased in the IL‐15 Tg mice following Listeria infection accompanied by sustained IL‐15 production. The increased CD44+CD8+ T cells in the infected IL‐15 Tg mice were not specialized to recognize Listeria‐specific antigen but produced a large amount of IFN‐γ in response to bystander stimulation exogenous IL‐15 in combination with IL‐12. Furthermore, Listeria‐specific Th1 response by CD4+ T cells was significantly augmented in the IL‐15 Tg mice compared with control mice following Listeria infection. In vivo depletion of the CD8+ T cells by anti‐CD8 monoclonal antibody and adoptive transfer of the T cells from naive IL‐15 Tg mice indicated that the CD8+ T cells functioned not only to eliminate bacteria at the early stage of infection but also to promote Th1 response to L. monocytogenes. Overexpression of IL‐15 shed light on a novel role of memory CD8+ T cells in early protection and promotion of Th1 response against a primary infection with L. monocytogenes.

Soluble Branched β-(1,4)Glucans from Acetobacter Species Show Strong Activities to Induce Interleukin-12 in Vitro and Inhibit T-helper 2 Cellular Response with Immunoglobulin E Production in Vivo

An Extracellular Polysaccharide, Ac-1, Produced By Acetobacter Polysaccharogenes Is Composed Of β-(1,4)GluCan With Branches Of Glucosyl Residues. We Found That Ac-1 Showed A Strong Activity To Induce Production Of Interleukin-12 P40 And Tumor Necrosis Factor-α By MacroPhage Cell Lines In Vitro. Cellulase Treatment Completely Abolished The Activity Of Ac-1 To Induce Tumor Necrosis Factor-α Production By Macrophages, Whereas Treatment Of Ac-1 With Polymyxin B Or Proteinase Did Not Affect The Activity. Results Of Experiments Using Toll-Like Receptor (Tlr) 4-Deficient Mice And Tlr4-Transfected Human Cell Line Indicated That Tlr4 Is Involved In Pattern RecogniTion Of Ac-1. In Vivo Administration Of Ac-1 Significantly Reduced The Serum Levels Of Ovalbumin (Ova)-Specific Ige And Interleukin-4 Production By T Cells In Response To Ova In Mice Immunized With Ova. Ac-1, A Soluble Branched β-(1,4)Glucan May Be Useful In Prevention And Treatment Of Allergic Disorders With Ige Production.

Dichotomous effect of a traditional Japanese medicine, Bu-zhong-yi-qi-tang on allergic asthma in mice

To determine the potentiality of prophylactic and/or therapeutic approaches using a traditional herbal medicine, Bu-zhong-yi-qi-tang (Japanese name: Hochu-ekki-to, HOT), for the control of allergic disease, we examined the effects of oral administration of HOT on a murine model of asthma allergic responses. When oral administration of HOT was begun at the induction phase immediately after OVA sensitization, eosinophilia and Th2-type cytokine production in the airway were reduced in OVA-sensitized mice following OVA inhalation. The serum levels of OVA-specific immunoglobulin (Ig)E and IgG1 were significantly decreased, whereas the level of OVA-specific IgG2a was increased. Interleukin (IL)-4 production by spleen T cells in response to OVA was significantly suppressed, while Interferon (IFN)-gamma production was increased in mice treated with HOT in the induction phase. On the other hand, HOT given in the eliciting phase induced a predominant Th2 response with increased IgE production in OVA-sensitized mice following OVA inhalation. These results suggest that the oral administration of HOT dichotomously modulates allergic inflammation in a murine model for asthma, thus offering a different approach for the treatment of allergic disorders.

Efficient induction of oral tolerance by fusing cholera toxin B subunit with allergen-specific T-cell epitopes accumulated in rice seed.

Cholera toxin B (CTB) subunit is an efficient mucosal carrier molecule for induction of oral tolerance to antigens and allergens. Here, T-cell epitopes of Cry j 1 and Cry j 2, major allergens in Japanese cedar pollen, were expressed in rice seed as a fusion protein with either CTB or rice glutelin as a control. Feeding mice with rice seed containing CTB-fused T-cell epitopes suppressed allergen-specific IgE responses and pollen-induced clinical symptoms at 50-fold lower doses of T-cell epitopes than required when using control seed. Our findings present a novel potential strategy for immunotherapy of type-I allergy.

Role of interleukin-15 in the development of mouse olfactory nerve

Interleukin (IL)‐15 interacts with components of the IL‐2 receptor (R) and exhibits T cell‐stimulating activity similar to that of IL‐2. In addition, IL‐15 is widely expressed in many cell types and tissues, including the central nervous system. We provide evidence of a novel role of IL‐15 in olfactory neurogenesis. Both IL‐15 and IL‐15Rα were expressed in neuronal precursor cells of the developing olfactory epithelium in mice. Adult IL‐15Rα knockout mice had fewer mature olfactory neurons and proliferating cells than wild‐type. Our results suggest that IL‐15 plays an important role in regulating cell proliferation in olfactory neurogenesis.