Abatacept inhibits T cell priming by inducing of a unique transcriptional profile that reduces their ability to activate antigen presenting cells

Objectives: The objective of this study was to determine at the phenotypic, functional and transcriptional level whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen presenting cells and is used to treat rheumatoid arthritis, induces a state of immunological tolerance in T cells and dendritic cells. Methods: We investigated the capacity of abatacept to regulate the development of antigen-specific immunological tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen specific T cell populations and CD11c+ antigen presenting cells. These were combined with detailed immunological and full genome transcriptional analysis. Results: We demonstrate that abatacept inhibits T cell activation, but does not render T cells anergic or lead to the generation of regulatory T cells. However, it induces a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells. Conclusion: This study provides a detailed insight into the mode of action of abatacept demonstrating that its effectiveness is not due to the induction of T cell tolerance but rather to a sustained inhibition of T cell activation that results in reduced functionality of antigen presenting cells, with significant implications for its clinical application. This article is protected by copyright. All rights reserved