Turner, Michael Stuart
(2005)
Regulation of MUC1-specific immunity by CD4+ T cells.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Finn, Olivera J | ojfinn@pitt.edu | OJFINN | | | Committee Member | Zeevi, Adriana | | | | | Committee Member | Hendricks, Robert L | | | | | Committee Member | Plevy, Scott E | | | | | Committee Member | Smithgall, Thomas E | | | |
|
| Date: |
14 December 2005 |
| Date Type: |
Completion |
| Defense Date: |
11 November 2005 |
| Approval Date: |
14 December 2005 |
| Submission Date: |
12 December 2005 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cancer; transgenic; Tregs; vaccine |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-12122005-154355/, etd-12122005-154355 |
| Date Deposited: |
10 Nov 2011 20:10 |
| Last Modified: |
15 Nov 2016 13:54 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10338 |
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