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Anergy This is a major mechanism inactivating peripheral autoreactive T-cell clones Anergic T-cell clones cannot respond to cognate antigenic stimuli: they do not produce IL-2 or IL-2R Multiple proposed mechanisms explain this block in T-cell activation ( Figure 3 ): Disruption of the interaction between the T-cell co-receptor CD28 and APC co-stimualtory molecules CD80/86 Interaction of CTLA-4 with CD80/86, negatively regulating T-cell activation T-cells displaying CD28 tend to be activated by APC, while T-cells displaying CTLA-4 tend to become anergic Under physiologic conditions, T-cells express CD28 on initial encounter with APC Shortly after such stimulation, they start displaying CTLA-4, which has a higher binding affinity than CD28 for CD80/86 than does CD28 CTLA-4 knockout mice develop profound lympho-proliferative disease Clinical Significance of CTLA-4 Rheumatoid arthritis is an autoimmune disease mainly affecting the joints CTLA-4 is used as a biologic response modifier to treat these patients, significantly reducing joint inflammation A fusion protein consisting of CTLA-4 and immunoglobulin (abatacept, belatacept) is used clinically in arthritis and after transplantation There is also interest in blocking CTLA-4 using monoclonal antibodies (e.g

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