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Abstract Number: 859

TGF-β3-Producing CD4+CD25–LAG3+ Regulatory T Cells Control B Cell Responses

Tomohisa Okamura1, Kaoru Morita1, Mariko Inoue1, Toshihiko Komai1, Yukiko Iwasaki1, Shuji Sumitomo1, Shinichiro Nakachi1, Hirofumi Shoda2, Keishi Fujio2 and Kazuhiko Yamamoto1, 1Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan, 2Department of Allergy and Rheumatology, The University of Tokyo, Tokyo, Japan

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: autoantibodies and regulatory cells, B cells, SLE, T cells

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Session Information

Session Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and associated with a wide range of clinical manifestations. Recent case-control association study suggests that polymorphisms in the early growth response gene-2 (EGR2), a zinc-finger transcription factor, influence SLE susceptibility in humans. In line with the observation, T-cell-specific Egr-2-deficient mice show lupus-like autoimmune disease. We previously described CD4+CD25–Foxp3– regulatory T cells (Treg) that characteristically express both lymphocyte activation gene 3 (LAG3, CD223) and Egr2 (hereinafter referred to as ‘LAG3+ Treg’). Therefore, we have examined whether LAG3+ Treg suppress the development of follicular helper T cell (TFH) and germinal center B cell (GCB), antibody production, and disease progression in lupus-prone MRL-Faslpr/lpr (MRL/lpr) mice.

Methods: B cells from C57BL/6 (B6) mice and helper T (Th) cells from OT-II mice were injected i.v. into Rag1KO mice in combination with or without LAG3+ Treg from B6, Egr2 conditional knockout (CKO) (Egr2fl/fl CD4-Cre+), or Fas-mutated B6/lpr mice. Mice were subsequently immunized with NP-OVA/alum 24 hr after the cell transfer. Mice were re-immunized with NP-OVA/alum 14 days after the first immunization. Serum anti-NP antibody levels were analyzed by ELISA, and splenocytes were analyzed by FACS 7 days after the re-immunization. To examine the therapeutic effects of LAG3+ Treg in lupus-prone mice, 8-week-old MRL/lpr mice were randomly assigned to specific treatment groups. Ten-week-old MRL/lpr mice in the treatment group were injected i.v. with LAG3+ Treg, CD4+CD25+Treg, or naïve T cells obtained from MRL/+ mice. Mice were sacrificed at 18 weeks of age to examine pathological alterations. Anti-ds DNA antibodies were measured by ELISA.

Results: Transfer of LAG3+ Treg from wild type (WT) mice, but not Egr2 CKO or B6/lpr mice, significantly suppressed NP-specific antibody responses and the development of GCB and TFH in Rag1KO mice transferred with B cells and OT-II Th cells. Interestingly, LAG3+ Treg produce high amounts of transforming growth factor-β3 (TGF-β3) in an Egr2- and Fas-dependent manner. Treatment with a TGF-β3 or FasL blocking antibody cancelled the suppressive activity of WT LAG3+ Treg. Adoptive transfer of LAG3+ Treg from control MRL/+ mice significantly suppressed the progression of nephritis and autoantibody production in MRL/lpr mice. In contrast, CD4+CD25+ Treg and naïve T cells from MRL/+ mice exhibited no significant therapeutic effect upon transfer to MRL/lpr mice. TGF-β3-blockade also abrogated the therapeutic effects of MRL/+ LAG3+ Treg in MRL/lpr mice.

Conclusion: These results clarified the molecular basis underlying TGF-β3-producing LAG3+ Treg-mediated B cell regulation, which indicated that LAG3+ Treg may be a suitable target for immune manipulation in autoantibody-mediated autoimmune diseases, including SLE.


Disclosure:

T. Okamura,
None;

K. Morita,
None;

M. Inoue,
None;

T. Komai,
None;

Y. Iwasaki,
None;

S. Sumitomo,
None;

S. Nakachi,
None;

H. Shoda,
None;

K. Fujio,
None;

K. Yamamoto,

UCB Pharma, Pfizer, Abbott, BMS, Roche, Chugai, Mitsubishi-Tanabe and Eisai ,

5,

UCB Pharma, Pfizer, Abbott, Santen, Mitsubishi-Tanabe and Eisai,

2.

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