The percentage of CD3+CD8?IL-21+ T cells in peripheral whole blood was significantly elevated in UC patients [76]. most analyzed types of IBD. Dysregulated mucosal immune response plays an important role in the pathogenesis of IBD. In recent years, many studies have recognized the crucial role of Tfh cells and IL-21 in the pathogenic process IBD. In this paper, we will discuss the role of Tfh cells and IL-21 in IBD pathogenesis. 1. Introduction T follicular helper (Tfh) cells are a specialized subset of T helper (Th) cells that can migrate into germinal center (GC) and help B cells to differentiate into antibody-producing plasma B cells and generate high-affinity antibodies [1]. In GC, Tfh cells provide survival and differentiation signals to B cells by cell-surface molecule crosstalk and the secretion of interleukin-21 (IL-21) [2]. Tfh cells play a central role in B cell activation and high-affinity antibody production; however, the dysfunction of Tfh may lead to allergic reactions, systemic autoimmune diseases, and chronic inflammation [3, 4]. Inflammatory bowel disease (IBD) is usually a group of chronic inflammatory disorders characterized by chronic relapsing inflammation of the gastrointestinal tract. Ulcerative colitis (UC) and Crohn’s disease (CD) are the major forms of inflammatory bowel disease (IBD) [5C7]. Although the exact etiology of IBD remains unclear, it is well established that genetic factors, environmental factors, microbiota, and immune response all contribute to this disease. Among them, the role of immune response in the development of IBD attracts many interests. In the gut of these patients, the tissue-damaging immune PF-06700841 tosylate response is initiated and regulated by the interplay between the immune and nonimmune cells [8C10]. Many studies have revealed that immune cells such as Th1, Th2, Treg, and Th17 contribute to the pathogenesis of IBD [11, 12]. In recent years, more and more studies have discovered the critical role of Tfh and IL-21 in initiating and shaping the pathologic process of IBD. In this article, we will discuss the pathogenic role of Tfh cells and IL-21 in IBD. 2. T Follicular Helper (Tfh) Cell Differentiation B lymphocytes and T lymphocytes are two important cell populations in the adaptive immune system. T cell-mediated cellular immunity and B PF-06700841 tosylate cell-mediated humoral immunity are two types of adoptive immunity. The generation of neutralizing antibodies by B lymphocytes is usually a critical step in immune response to viral or bacterial infections, which is one of the two types of adoptive immunity. This process needs direct crosstalk between activated B and T cells in a specialized structure called germinal center (GC). The germinal center (GC) formation is critical in the generation of high-affinity antibodies and long-lived plasma cells, which is the base of humoral immune responses against pathogen contamination. CD4+ helper T cells have been found to play critical roles in this progress [13C15]. In early 2000s, a new subset of CD4+ helper T cells termed as T follicular helper (Tfh) cells have been identified as the key cells necessary for regulating GC formation and B cell function. Tfh cells are the important mediator in regulating humoral immune response via direct interactions with B cells [16C18]. The Tfh cells have many unique features, such as the expression of CXC chemokine receptor 5 (CXCR5), programmed death 1 (PD-1), inducible costimulatory molecule (ICOS), and B cell lymphoma 6 (BCL-6) and PF-06700841 tosylate the production of IL-21 [19C21]. Tfh cell differentiation is usually a complex and multistage process (Physique 1). In the beginning, naive CD4+ T cell are stimulated by DCs in a T cell zone of secondary lymphoid tissues and become to pre-Tfh; then, guided by chemokines, pre-Tfh migrates to the T-B border and interacts with antigen-specific B cells in B cell follicles; further activation and antigen presentation by B cells provide help to pre-Tfh cells to become GC Tfh cells. GC Tfh cells can help B cells to differentiate into antibody-secreting plasma cells in GCs [22C24]. Tfh cell differentiation is usually regulated by numerous factors such as extracellular cytokines, cell-surface molecule interactions, multiple transcription factors, and microRNAs [25, 26]. Open in a separate PF-06700841 tosylate window Physique 1 The differentiation of Tfh cells. Naive CD4+ T cells are primed by MHC/antigen conversation with DCs and differentiate to pre-Tfh cells; then, pre-Tfh cells migrate to the T-B border and interact with cognate B cells; finally, interactions between pre-Tfh cells and B cells lead to the formation of GC Tfh cells. 2.1. Cytokines 2.1.1. IL-6 Cytokine signaling play a critical MGC102953 role in driving naive CD4+ T cells to differentiate into unique effector T cell subsets. Numerous studies have reported the important role IL-6 in PF-06700841 tosylate regulating Tfh cell differentiation [27]. IL-6 can promote Bcl-6 expression and Tfh cell differentiation by regulating transmission transducer.