Amelioration of autoimmune arthritis by adoptive transfer of Foxp3-expressing regulatory B cells is associated with the Treg/Th17 cell balance
Park et al. J Transl Med
Amelioration of autoimmune arthritis by adoptive transfer of Foxp3-expressing regulatory B cells is associated with the Treg/ Th17 cell balance
Mi Kyung Park 0 1 5
Young Ok Jung 1 4
SeonY‑eong Lee 0 1 5
Seung Hoon Lee 0 1 5
Yu Jung Heo 0 1 5
Eun Kyung Kim 0 1 5
Hye Jwa Oh 0 1 5
Young Mee Moon 0 1 5
HyeJ‑in Son 0 1 5
Min Jung Park 0 1 5
Sung Hwan Park 1 3
Ho Youn Kim 1 3
Mi La Cho 0 1 5
Jun Ki Min 1 2 6 7
0 The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea , 505 Banpo‐dong, Seocho‐gu, Seoul 137‐040 , South Korea
1 to this work
2 Bucheon St. Mary's Hospital, Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea , 327 Sosa‐ro, Wonmi‐gu, Bucheon, Gyeonggi‐do 420‐717 , South Korea
3 Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea , Seoul , South Korea
4 Division of Rheumatology, Department of Inter‐ nal Medicine, Hallym University Kang‐Nam Sacred Heart Hospital , Seoul , South Korea
5 The Rheumatism Research Center, Catholic Research Institute of Medi‐ cal Science, The Catholic University of Korea , 505 Banpo‐dong, Seocho‐gu, Seoul 137‐040 , South Korea
6 Division of Rheumatology, Department of Internal Medicine, College of Medicine, Holy Family Hospital, Rheumatism Research Center (RhRC), Catholic Research Institute of Medical Science, The Catholic University of Korea , Seoul , South Korea
7 Bucheon St. Mary's Hospital, Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea , 327 Sosa‐ro, Wonmi‐gu, Bucheon, Gyeonggi‐do 420‐717 , South Korea
Background: Foxp3 is a key regulator of the development and function of regulatory T cells (Tregs), and its expression is thought to be T cell‑ restricted. We found that B cells in mice can express Foxp3 and B cells expressing Foxp3 may play a role in preventing the development of collagen‑ induced arthritis (CIA) in DBA/1J mice. Methods: Foxp3 expression was modulated in CD19+ B cells by transfection with shRNA or using an over‑ expression construct. In addition, Foxp3‑ transfected B cells were adoptively transferred to CIA mice. We found that LPS or antiIgM stimulation induced Foxp3 expression in B cells. Foxp3‑ expressing B cells were found in the spleens of mice. Results: Over‑ expression of Foxp3 conferred a contact‑ dependent suppressive ability on proliferation of responder T cells. Down‑ regulation of Foxp3 by shRNA caused a profound induction in proliferation of responder T cells. Adoptive transfer of Foxp3+CD19+ B cells attenuated the clinical symptoms of CIA significantly with concomitant suppression of IL‑ 17 production and enhancement of Foxp3 expression in CD4+ T cells from splenocytes. Conclusion: Our data indicate that Foxp3 expression is not restricted to T cells. The expression of Foxp3 in B cells is critical for the immunoregulation of T cells and limits autoimmunity in a mouse model.
Foxp3; Regulatory B cell; Th17; Arthritis
Background
B cells exert a variety of immune functions, including the
production of immunoglobulins (Igs) and cytokines, the
presentation of antigens, and the regulation of dendritic
cells [
1–4
]. B cells are generally considered to positively
regulate immune responses by producing
antigen(Ag)specific antibodies (Abs) and inducing CD4+ T cell
activation [5]. B cells are involved in the development of
several autoimmune disorders through the production of
pathogenic Igs [
6, 7
]. Especially, immune-regulatory roles
of B cells in autoimmune diseases have been reported
that specific B cell subsets regulate immune responses
and participate in the induction of immune tolerance [
8,
9
].
The existence of B cells with regulatory properties
has been widely reported [
10–14
]. Several studies have
shown that absence of B cells exacerbated pathologic
inflammatory responses in autoimmune diseases [
12, 14
].
B cell-deficient (μMT) mice lacked the capacity to resolve
inflammation in Experimental Autoimmune
Encephalomyelitis [1]. Mizoguchi and colleagues introduced the
term ‘regulatory B cells (Bregs)’ to designate B cells with
negative regulatory properties [
15
]. Experimental studies
have demonstrated that the absence or loss of Bregs
exacerbates symptoms in several experimental autoimmune
disease model including collagen-induced arthritis (CIA)
[
15–21
]. Additionally, Bregs showed therapeutic
properties in autoimmune arthritis mice models [
18, 22
].
Rheumatoid arthritis (RA) is a debilitating
autoimmune disease characterized by chronic inflammation
and destruction of the joints has been considered to be
a Th1 and/or Th17-mediated disease. However, B cells
also play important roles in the pathogenesis of RA. B
cells present within the synovial membrane of affected
joints are involved directly in sustained inflammation in
the rheumatoid synovium [
3
], (...truncated)