MUC1 is a large glycoprotein that is expressed on ductal epithelial cells and also the majority of epithelial adenocarcinomas. Dysregulated expression of aberrantly glycoslyated MUC1 in carcinomas allows tumor-specific recognition of MUC1-derived epitopes by antibodies and T lymphocytes. However, despite the ability of CTL to specifically recognize and kill MUC1+ tumor cells, immune responses in cancer patients fail to prevent tumor progression. The failure of patients immune systems to eradicate MUC1+ tumors has been linked with their inability to mount MUC1-specific helper T cell responses.
Here we show that CD4+ T cells play a central role in both the enhancement and suppression of MUC1-specific immune responses. Using MUC1-Tg mice as a model for tolerance to self-expressed MUC1, we show that MUC1-specific regulatory T cells (Tregs) respond to stimulation with MUC1 in the absence of a CD4+ T helper response. The Treg:Th imbalance in MUC1-Tg mice causes the suppression of MUC1-specific immunity. This suppression can be overcome by providing functional Th cells from WT mice. To focus our studies on MUC1-specific CD4+ T cells, we created a TCR-transgenic mouse whose CD4+ T cells are specific for an MHC Class II-restricted epitope derived from unglycosylated MUC1. Using these mice, we have confirmed that adoptive transfer of MUC1-specific CD4+ T replaces the MUC1-specific T cell help that is missing in MUC1-Tg mice and restores their ability to respond to MUC1 vaccines. This work shows that the generation of CD4 helper T cell responses is critical to establishing effective immunity to MUC1+ cancers.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12122005-154355 |
| Date | 14 December 2005 |
| Creators | Turner, Michael Stuart |
| Contributors | Adriana Zeevi, Ph.D., Robert L. Hendricks, Ph.D., Olivera J. Finn, Ph.D., Thomas E. Smithgall, Ph.D., Scott E. Plevy, M.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12122005-154355/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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