Understanding control of T cell responses by CTLA-4

TL;DRAbstract

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 C

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