Interleukin-10-producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis

Shinichiro Nakachi, Shuji Sumitomo, Yumi Tsuchida, Haruka Tsuchiya, Masanori Kono, Rika Kato, Keiichi Sakurai, Norio Hanata, Yasuo Nagafuchi, Shoko Tateishi, Hiroko Kanda, Tomohisa Okamura, Kazuhiko Yamamoto, Keishi Fujio

Regulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4(+)CD25(-)LAG3(+) T cells (LAG3(+) Tregs) and their association with rheumatoid arthritis (RA). LAG3(+) Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3(+) Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4(+) T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays. LAG3(+) Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25(+) Tregs. Cell-to-cell contact was required for the suppressive function of LAG3(+) Tregs. The frequency of LAG3(+) Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3(+) Tregs significantly increased after 6 months of abatacept treatment, whereas CD25(+) Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4(+) T cells, and abatacept-treated CD4(+) T cells exhibited suppressive activity. IL-10-producing LAG3(+) Tregs are associated with the immunopathology and therapeutic response in RA. LAG3(+) Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.