Amelioration of autoimmune arthritis by adoptive transfer of Foxp3-expressing regulatory B cells is associated with the Treg/Th17 cell balance

Journal of Translational Medicine, Jun 2016

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 anti-IgM 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.

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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)


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Mi Park, Young Jung, Seon-Yeong Lee, Seung Lee, Yu Heo, Eun Kim, Hye Oh, Young Moon, Hye-Jin Son, Min Park, Sung Park, Ho Kim, Mi La Cho, Jun Min. Amelioration of autoimmune arthritis by adoptive transfer of Foxp3-expressing regulatory B cells is associated with the Treg/Th17 cell balance, Journal of Translational Medicine, 2016, pp. 191, 14, DOI: 10.1186/s12967-016-0940-7