title: The Emerging Role of Interleukin-21 in Transplantation.
abstract: Since its discovery in 2000, IL-21 has been shown to play critical roles in the regulation of both innate and adaptive immune responses. IL-21 is produced predominantly by multiple effector CD4+T-cell types [T helper 17 (Th17), follicular helper T (TFH), and other activated CD4+cells] and NKT cells. In addition to T cell receptor (TCR) signals, the production of IL-21 by activated CD4+T cells is intricately regulated by various extrinsic factors and intrinsic molecules, such as IL-6, IL-21, ICOS, Stat3, IRF4, and Batf. Because IL-21 receptor (IL-21R) is broadly expressed on T, B, NK, and dentritic cells (DCs), IL-21 signaling via Jak-Stat and other pathways has direct pleiotropic effects on their proliferation, differentiation, and effector function. For instance, while Th17 and TFHcells produce IL-21, IL-21 also facilitates the development of these cells. IL-21-producing TFHcells are important for the generation and maintenance of germinal centers, and control the differentiation of germinal center B cells and immunoglobulin production. Thus, IL-21R deficiency or IL-21 neutralization with IL-21R-Fc fusion protein prevents B cell-mediated autoimmunity in lupus-prone BXSB.B6-Yaa+or MRL-Faslprmouse models, respectively. IL-21 also enhances expansion and cytotoxicity of CD8+effector T cells. During chronic lymphocytic choriomeningitis viral infection, chronic IL-21 production by antigen-specific CD4+T cells is needed to sustain CD8+T cell function for viral control. IL-21 is also required for the development of T cell-mediated type 1 diabetes in NOD mice, possibly through sustaining effector T cell function in a similar manner. Recently, two papers have shown that IL-21R-Fc prevents both auto- and allo-immune responses after islet transplantation. A timely discussion is thus needed to address the immune actions of IL-21 as well as the therapeutic potential of targeting IL-21 in transplantation.
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA ; Department of Cardiovascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
authors.forename: Aini
authors.initials: A
authors.lastname: Xie
authors.forename: Eric Dale
authors.initials: ED
authors.lastname: Buras
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xia
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
keywords: B cells; IL-21; T cells; Tolerance; Transplantation