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Understanding control of T cell responses by CTLA-4

Baker, Jennifer (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

Cytotoxic T Lymphocyte Associate Antigen 4 (CTLA-4) is an important negative regulator of T-cell activation. The protein is expressed in activated T-cells and can also be found in regulatory T-cells. The mechanism of action of this protein remains controversial; it has typically been associated with a cell intrinsic negative signal however, there is increasing evidence that CTLA-4 may act as an effector molecule. Surprisingly, we find that blocking CTLA-4 in a model of T-cell activation driven by ligand-expressing transfectants has no effect on either proliferation or cytokine production, suggesting that CTLA-4 doesn’t inhibit in this setting. In contrast, blocking CTLA-4 in a dendritic cell based assay enhances proliferation and cytokine production, only when the amount of co-stimulation is limiting. In these experiments CTLA-4 function correlates with decreased expression of B7 ligands on dendritic cells consistent with the removal of ligands by CTLA-4. Furthermore, the addition of CTLA-4 transfected Jurkat cells acts to suppress T cell responses consistent with a role for CTLA-4 as an effector of suppression. Overall our data do not support a role for CTLA-4 in delivering a ligand-dependent cell-intrinsic negative signal and instead suggest a role for CTLA-4 as an effector molecule which inhibits co-stimulation by APC.

Type of Work:Ph.D. thesis.
Supervisor(s):Sansom, David
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Clinical and Experimental Medicine
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:3788
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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