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