Cell contact is required for efficient transmission of human T cell leukemia virus- type 1 (HTLV-I) between cells and between individuals, because naturally infected lymphocytes produce virtually no cell-free infectious HTLV-I particles. However, the mechanism of cell-to-cell spread of HTLV-I is not understood. We show here that cell contact rapidly induces polarization of the cytoskeleton of the infected cell to the cell-cell junction. HTLV-I core (Gag protein) complexes and the HTLV-I genome accumulate at the cell-cell junction and are then transferred to the uninfected cell. Other lymphotropic viruses, such as HIV-1, may similarly subvert normal T cell physiology to allow efficient propagation between cells.

Upon microbial infection, specific Th1 or Th2 responses develop depending on the type of microbe. Here, we demonstrate that different microbial compounds polarize the maturation of human myeloid dendritic cells (DCs) into stably committed Th1 cell-promoting (DC1) or Th2 cell-promoting (DC2) effector DCs that polarize Th cells via different mechanisms. Protein extract derived from the helminth Schistosoma mansoni induced the development of DC2s that promote the development of Th2 cells via the enhanced expression of OX40 ligand. Likewise, toxin from the extracellular bacterium Vibrio cholerae induced development of DC2s as well, however, via an OX40 ligand-independent, still unknown mechanism. In contrast, toxin from the intracellular bacterium Bordetella pertussis induced the development of DC1s with enhanced IL-12 production, which promotes a Th1 cell development. Poly(I:C) (dsRNA, mimic for virus) induced the development of extremely potent Th1-inducing DC1, surprisingly, without an enhanced IL-12 production. The obtained DC1s and DC2s are genuine effector cells that stably express Th cell-polarizing factors and are unresponsive to further modulation. The data suggest that the molecular basis of Th1/Th2 polarization via DCs is unexpectedly diverse and is adapted to the nature of the microbial compounds.

To clarify the status of tax gene, we analyzed human T-cell leukemia virus type-I (HTLV-I) associated cell lines and fresh adult T-cell leukemia (ATL) cells. We compared 2 types of HTLV-I associated cell lines: one was derived from leukemic cells (leukemic cell line) and the other from nonleukemic cells (nonleukemic cell line). Although all nonleukemic cell lines expressed Tax, it could not be detected in 3 of 5 leukemic cell lines, in which nonsense mutation or deletion (60 bp) of tax genes, and DNA methylation in 5-LTR were identified as the responsible changes. We found such genetic changes of the tax gene in 5 of 47 fresh ATL cases (11%). The tax gene transcripts could be detected in 14 of 41 fresh ATL cases (34%) by RT-PCR. In ATL cases with genetic changes that could not produce Tax protein, the tax gene was frequently transcribed, suggesting that such cells do not need the transcriptional silencing. Although DNA methylation of 5-LTR was detected in the fresh ATL cases (19 of 28 cases; 68%), the complete methylation associated with transcriptional silencing was observed only in 4 cases. Since partial methylation could not silence the transcription, and the tax gene transcription was not detected in 27 of 41 cases (66%), the epigenetic change(s) other than DNA methylation is considered to play an important role in the silencing.

TSLP released from human breast cancer cells promotes OX40L expression on DCs, and these OX40L-expressing DCs drive development of inflammatory Th2 cells which promote breast tumor development.

Human T-cell leukemia virus type I (HTLV-I IntroductionAdult T-cell leukemia (ATL) is an aggressive malignancy of CD4 ϩ T cells, and its development is closely associated with human T-cell leukemia virus type I (HTLV-I) infection. [1][2][3] In vitro, HTLV-I transforms primary human CD4 ϩ T cells in interleukin-2 (IL-2)-dependent and IL-2-independent manners. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral Tax protein plays a crucial role in these processes. For instance, like HTLV-I, Tax immortalizes primary human CD4 ϩ T cells in vitro and transforms rat fibroblast cell lines. 4,5 In addition, Tax inhibits apoptosis induced by various stimuli in T-cell lines. 6 Tax activates viral gene expression through the binding sequence for cAMP response element binding protein (CREB)/ activating transcription factor (ATF) in the 21-bp repeats of the HTLV-I long terminal repeat (LTR). Tax has been shown to activate the expression of a number of cellular genes through several distinct transcription factors, such as NF-B/Rel, AP-1, and serum response factor. 7-9 The cellular genes induced by Tax include cytokines/chemokines (IL-1␣, IL-6, IL-8, tumor necrosis factor-␤, monocyte chemoattractant protein-1, granulocyte macrophage-colony stimulating factor, and granulocyte colonystimulating factor), their receptors (the ␣ chain of IL-2 receptor [IL-2R] and IL-15R), cell adhesion molecule (OX40), matrix metalloproteinase (MMP-9), apoptosis inhibitor (Bcl-x L ), and G1-cyclins (cyclin D1 and cyclin D2). 7,10-21 The transcriptional activation of cellular genes, including those listed above, by Tax is thought to contribute to deregulated proliferation of HTLV-Iinfected cells.Accumulating evidence suggests that activation of cellular genes by Tax through NF-B is a critical process in the transforming activity as well as the inhibition of apoptosis. For instance, a Tax mutant inactive for NF-B cannot immortalize primary human T cells in vitro. 22 NF-B2, a member of the IB protein family, abrogates the transformation of a rat fibroblast cell line by Tax. 5 Tax inhibits apoptosis induced by IL-2 withdrawal in mouse factor-dependent T-cell lines, and such inhibition correlates with the activation of NF-B and induction of the antiapoptotic gene Bcl-x L through the NF-B pathway. 23,24 In resting T cells, NF-B is sequestered in the cytoplasm in an inactive form by association with an inhibitory IB subunit. Activation of NF-B generally involves phosphorylation and degradation of IBs, followed by nuclear translocation of NF-B and subsequent activation of the genes containing NF-B binding sites. IBs are phosphorylated by a multisubunit IB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK␣ and IKK␤, and a noncatalytic subunit, IKK␥/NEMO. Tax Reprints: Naoki Mori, Department of Virology, Faculty of Medicine, University of the Ryukyus, 207, Uehara, Nishihara, Okinawa 903-0215, Japan; e-mail: n-mori@med.u-ryukyu.ac.jp.The publication costs of this ar...