Abatacept inhibition of T cell priming in mice by induction of a unique transcriptional profile that reduces their ability to activate antigen‐presenting cells

A Patakas, RR Ji, W Weir, SE Connolly… - Arthritis & …, 2016 - Wiley Online Library
A Patakas, RR Ji, W Weir, SE Connolly, RA Benson, SG Nadler, JM Brewer, IB McInnes…
Arthritis & rheumatology, 2016Wiley Online Library
Objective To determine at the phenotypic, functional, and transcriptional levels whether
abatacept, a CTLA‐4Ig molecule that binds with high affinity to CD80/86 on antigen‐
presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of
immunologic tolerance in T cells and dendritic cells in mice. Methods We investigated the
capacity of abatacept to regulate the development of antigen‐specific immunologic
tolerance in vivo using murine models of priming and tolerance to generate highly purified …
Objective
To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA‐4Ig molecule that binds with high affinity to CD80/86 on antigen‐presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.
Methods
We investigated the capacity of abatacept to regulate the development of antigen‐specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen‐specific T cell populations and CD11c+ APCs. These were combined with detailed immunologic and full genome transcriptional analyses.
Results
We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced 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 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 APCs, with significant implications for its clinical application.
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