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  • Title: Tat mammaglobin fusion protein transduced dendritic cells stimulate mammaglobin-specific CD4 and CD8 T cells.
    Author: Viehl CT, Tanaka Y, Chen T, Frey DM, Tran A, Fleming TP, Eberlein TJ, Goedegebuure PS.
    Journal: Breast Cancer Res Treat; 2005 Jun; 91(3):271-8. PubMed ID: 15952060.
    Abstract:
    Proteins can be efficiently introduced into cells when fused to a protein transduction domain, such as Tat from the human immunodeficiency virus. We recently reported that dendritic cells transduced with a Tat fusion protein containing the extracellular domain of Her2/neu (Tat-Her2/neu) induced CD8 cytotoxic T lymphocytes (CTL) that specifically lysed Her2/neu-expressing breast and ovarian cancer cells. In the current study we further investigated the mechanism of protein transduction, utilizing the breast cancer-associated protein, mammaglobin-A, which is expressed in about 80% of breast cancers. Using a Tat-mammaglobin fusion protein, we tested the ability of Tat-mammaglobin transduced dendritic cells to stimulate antigen-specific CD4 and CD8 T cells. Low levels of serum considerably improved protein transduction as determined by Western blot, and also improved presentation of antigenic peptide as evidenced by functional studies using antigen-specific T cells. Confocal microscope analyses of antigen-presenting cells (APC) incubated with Tat-mammaglobin showed localized distribution in addition to diffuse distribution in the cytosol. In contrast, mammaglobin lacking Tat showed only a localized distribution. Simultaneous incubation with both proteins resulted in overlapping localized distributions, suggesting Tat fusion proteins are processed through both the MHC class I and class II pathways. Indeed, stimulation of T cells with Tat-mammaglobin transduced dendritic cells led to an expansion of mammaglobin-specific CD4 T helper-1 lymphocytes along with CD8 CTL. We conclude that Tat-mammaglobin transduced dendritic cells can induce both CD4 and CD8 mammaglobin-specific T cells. These findings could be further exploited for the development of a mammaglobin-based vaccine for breast cancer.
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