The cytokine inducible SH2-domain protein (CISH) is a well-known STAT5 target gene, but its role in the immune system remains uncertain. In this study, we found that CISH is predominantly induced during dendritic cell (DC) development from mouse bone marrow (BM) cells and plays a crucial role in type 1 DC development and DC-mediated CTL activation. CISH knockdown reduced the expression of MHC class I, co-stimulatory molecules and pro-inflammatory cytokines in BMDCs. Meanwhile, the DC yield was markedly enhanced by CISH knockdown via cell-cycle activation and reduction of cell apoptosis. Down-regulation of cell proliferation at the later stage of DC development was found to be associated with CISH-mediated negative feedback regulation of STAT5 activation. In T-cell immunity, OT-1 T-cell proliferation was significantly reduced by CISH knockdown in DCs, whereas OT-2 Tcell proliferation was not affected by CISH knockdown. CTLs generated by DC vaccination were also markedly reduced by CISH knockdown, followed by significant impairment of DCbased tumor immunotherapy. Taken together, our data suggest that CISH expression at the later stage of DC development triggers the shutdown of DC progenitor cell proliferation and facilitates DC differentiation into a potent stimulator of CTLs. Key words: CISH . cytotoxic T lymphocyte (CTL). IntroductionDCs are the most well-known professional antigen-presenting cells, which play a key role in priming antigen-specific adaptive immunity and controlling immune homeostasis [1,2]. DCs have been studied widely because of their Th1-polarizing immunogenicity when inoculated in vivo, demonstrating their potential for use in the development of therapeutic cancer vaccines [3][4][5]. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a cytokine essential for DC development from hematopoietic progenitor cells [6]. However, the molecular mechanisms underlying GM-CSF-mediated DC development in association with Th1-polarizing immunogenicity are poorly understood.GM-CSF exerts its biological functions by phosphorylating at least two distinct domains in the b-chain of its receptor. One of these domains induces the activation of mitogen-activated 58protein kinases (MAPKs), which is followed by the activation of the PI3K/Akt/p21waf-1 pathway, and the other domain mediates activation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling pathway [7]. When activated, STAT5 migrates into the nucleus after mutual phosphorylation and dimerization, and then binds to specific DNAbinding sites, followed by the expression of STAT5 target genes [8]. STAT5 is well established for its diverse activities in cell proliferation, renewal of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells, and moderating cell differentiations [9].Cytokine inducible SH2-domain protein (CISH) was first reported as an immediate early gene induced by GM-CSF, interleukin (IL)-2, IL-3 and erythropoietin (EPO) in hematopoietic cells [10]. Later, CISH was identified as a S...

We define the affine index polynomial of a flat virtual knot in a similar way as the case of a virtual knot, and show that it is described by the affine index polynomial of any overlying virtual knot. Let K be a virtual knot, and F the underlying flat virtual knot of K. Then we have necessary conditions for the invariant of F about invertibility and amphicheirality of K and F. As applications of the invariant, we raise examples such as (1) F is non-invertible, and (2) K is non-amphicheiral. We also give an alternative proof of a fact that Hrencecin and Kauffman's flat virtual knots are mutually distinct, which is originally proved by Im, Lee and Son.

In this paper, we give several simple criteria to detect possible periods and linking numbers for a given virtual link. We investigate the behavior of the generalized Alexander polynomial [Formula: see text] of a periodic virtual link [Formula: see text] via its Yang–Baxter state model given in [L. H. Kauffman and D. E. Radford, Bi-oriented quantum algebras and a generalized Alexander polynomial for virtual links, in Diagrammatic Morphisms and Applications, Contemp. Math. 318 (2003) 113–140, arXiv:math/0112280v2 [math.GT] 31 Dec 2001].

In this paper, we give a relationship between the virtual Alexander polynomial of a periodic virtual knot and that of its factor knot. As an application, we improve Im–Lee's table of possible periods of 117 virtual knots with classical crossings ≤ 4 in Jeremy Green's table. In particular, we prove that the virtual knots 4.1 and 4.77 have the actual period 2 and no others, and the virtual knot 4.99 has the actual period 2.

In this paper, we provide two new congruences of the generalized Alexander polynomial [Formula: see text] for periodic virtual links [Formula: see text]. We use the Yang–Baxter state model of [Formula: see text] introduced by Kauffman and Radford.