First report of ophidiomycosis in Asia caused by Ophidiomyces ophiodiicola in captive snakes in Japan.

Ophidiomycosis is an emerging infectious disease caused by the fungus Ophidiomyces ophiodiicola, which has been affecting wild and captive snakes in North America, Europe, and Australia. We report 12 cases of suspected ophidiomycosis in captive colubrid snakes in Japan. Pathological and microbiological examinations were performed, and the results confirmed the diagnosis of ophidiomycosis in two snakes, which indicated that the remaining sympatrically raised snakes also had ophidiomycosis since they exhibited similar lesions. This is the first report of ophidiomycosis in Asia caused by O. ophiodiicola. To prevent the expansion of ophidiomycosis in the natural environment in Japan, there is a need to evaluate the ophidiomycosis carrier status of imported snakes, the pathogenicity of the infection in native snakes, and the prevalence and distribution of O. ophiodiicola in wild and captive snakes. Measures also must be taken to prevent endemicity globally.

Cross-linking of 4-1BB up-regulates IL-13 expression in CD8(+) T lymphocytes.

4-1BB, one of co-stimulatory molecules, is a member of TNF receptor superfamily and expressed on T cells upon TCR ligation. We have shown that 4-1BB is a co-stimulatory molecule enhancing cell cycle progression and inhibiting activation-induced cell death of CD8+ T cells by enhancing TCR signaling pathways. Here, we first report that the cross-linking of 4-1BB increased the expression of IL-13 mRNA and protein, and its secretion apparently via calcineurin, a Ca2+/calmodulin-dependent phosphatase. Ligation of 4-1BB with p815-m-4-1BBL evoked intracellular Ca2+ level in CD8+ T cells. CD8+ T cells express IL-13 receptor alpha1 mRNA. Incubation with anti-IL-13 blocking mAb reduced proliferation of CD8+ T cells enhanced by 4-1BB, and the treatment of CD3/4-1BB-ligated CD8+ T cells with recombinant IL-13 enhances cell proliferation, indicating that 4-1BB-induced IL-13 expression is partially responsible for the CD8+ T cell expansion in an autocrine or paracrine manner.

The therapeutic potential of 4-1BB (CD137) in cancer.

Techniques for modulating immune cells for cancer therapy have been widely studied. One key approach that is being clinically tested is developing tumor-destructive cell-mediated immune responses by regulating co-stimulatory molecules. 4-1BB (CD137), a member of the TNF receptor family, is expressed following activation of T and NK cells. Recently, it has been reported that DCs also express 4-1BB. Cross-linking of 4-1BB provides a potent co-stimulatory signal for lymphocytes via signal transduction pathways that modulate a number of cellular responses. One remarkable response is stimulation of anti-tumor activity in vivo and in vitro. We here review the potential role of 4-1BB in cancer immunotherapy focusing on the cellular and molecular mechanisms involved.

Cross-linking of 4-1BB activates TCR-signaling pathways in CD8+ T lymphocytes.

Cross-linking of 4-1BB, a member of the TNFR family, increased tyrosine phosphorylation of TCR-signaling molecules such as CD3epsilon, CD3zeta, Lck, the linker for activation of T cells, and SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76). In addition, incubation of activated CD8+ T cells with p815 cells expressing 4-1BBL led to redistribution of the lipid raft domains and Lck, protein kinase C-theta;, SLP-76, and phospholipase C-gamma1 (PLC-gamma1) on the T cell membranes to the areas of contact with the p815 cells and recruitment of 4-1BB, TNFR-associated factor 2, and phospho-tyrosine proteins to the raft domains. 4-1BB ligation also caused translocation of TNFR-associated factor 2, protein kinase C-theta;, PLC-gamma1, and SLP-76 to detergent-insoluble compartments in the CD8+ T cells, and cross-linking of 4-1BB increased intracellular Ca2+ levels apparently by activating PLC-gamma1. The redistribution of lipid rafts and Lck, as well as translocation of PLC-gamma1, and degradation of IkappaB-alpha in response to 4-1BB were inhibited by disrupting the formation of lipid rafts with methyl-beta-cyclodextrin. These findings demonstrate that 4-1BB is a T cell costimulatory receptor that activates TCR-signaling pathways in CD8+ T cells.

4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes.

4-1BB, a T cell co-stimulatory receptor, prolongs the survival and multiplication of CD4 T cells. Cross-linking 4-1BB stimulated expression of the anti-apoptotic genes bcl-XL and bcl-2, as well as of cyclins D2 and E, and inhibited expression of the cyclin-dependent kinase (cdk) inhibitor p27kip1. Ova-activated CD4 T cells of 4-1BB-deficient/DO11.10 TCR transgenic mice survived less well and underwent less expansion than cells of wild type DO11.10 TCR transgenic mice. These findings demonstrate that 4-1BB is a co-stimulatory molecule for CD4 T cell survival and expansion in vivo.

4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1.

The T cell costimulatory receptor 4-1BB enhances cell cycle progression and proliferation of CD8(+) T cells in both an IL-2-dependent and -independent manner. In these studies, 4-1BB costimulation was shown to increase cyclin D2, D3, and E expression, and concomitantly down-regulate the expression of the cyclin-dependent kinase inhibitor p27(kip1). 4-1BB increases cyclin D2 transcription via mitogen-activated/extracellular signal-regulated kinase-1/2 and LY294002-sensitive phosphatidylinositol 3-kinase (PI3K) signaling pathways. In addition, 4-1BB up-regulates cyclin D2 translation via PI3K/Akt/mammalian target of rapamycin (mTOR) pathways, presumably triggered by IL-2/IL-2 receptor ligation. The enhanced cyclin D2 and D3 expression initiates up-regulation of cyclin E expression and down-regulation of p27(kip1). Our results suggest a role for cyclin D2, D3, and E, and p27(kip1) proteins in the 4-1BB-mediated cell cycle progression of CD8(+) T cells in vivo.

4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1.

4-1BB, a T cell costimulatory receptor, prolongs CD8(+) T cell survival. In these studies, 4-1BB stimulation was shown to increase expression of the antiapoptotic genes bcl-x(L) and bfl-1 via 4-1BB-mediated NF-kappaB activation. This signaling pathway was specifically inhibited by PDTC and was different from the pathways that enhanced CD8(+) T cell proliferation. The results suggest a role for the antiapoptotic activities of Bcl-x(L) and Bfl-1 proteins in 4-1BB-mediated CD8(+) T cell survival in vivo.