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Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells
Author(s) -
Patakas Agapitos,
Ji RuiRu,
Weir William,
Connolly Sean E.,
Benson Robert A.,
Nadler Steven G.,
Brewer James M.,
McInnes Iain B.,
Garside Paul
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39470
Subject(s) - abatacept , cd80 , priming (agriculture) , cd86 , t cell , antigen presenting cell , microbiology and biotechnology , antigen , immunology , cd11c , immune tolerance , dendritic cell , biology , cell , immune system , cd40 , cytotoxic t cell , in vitro , phenotype , antibody , biochemistry , rituximab , botany , germination , gene
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.