The Role of T Follicular Helper Cells and Interleukin-21 in the Pathogenesis of Inflammatory Bowel Disease

Sun, Lulu; Kong, Ruixue; Li, Hua; Wang, Dashan

doi:https://doi.org/10.1155/2021/9621738

Gastroenterology Research and Practice

On this page

Abstract Introduction Conclusion Conflicts of Interest Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2021 | Article ID 9621738 | https://doi.org/10.1155/2021/9621738

The Role of T Follicular Helper Cells and Interleukin-21 in the Pathogenesis of Inflammatory Bowel Disease

Lulu Sun,¹Ruixue Kong,¹Hua Li,¹and Dashan Wang²

Academic Editor: Paul A. Rufo

Received19 Apr 2021

Revised17 Jul 2021

Accepted04 Aug 2021

Published23 Aug 2021

Abstract

T follicular helper (Tfh) cells represent a novel subset of CD4⁺ T cells which can provide critical help for germinal center (GC) formation and antibody production. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), programmed death 1 (PD-1), inducible costimulatory molecule (ICOS), B cell lymphoma 6 (BCL-6), and the secretion of interleukin-21 (IL-21). Given the important role of Tfh cells in B cell activation and high-affinity antibody production, Tfh cells are involved in the pathogenesis of many human diseases. Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases characterized by symptoms such as diarrhea, abdominal pain, and weight loss. Ulcerative colitis (UC) and Crohn’s disease (CD) are the most studied types of IBD. Dysregulated mucosal immune response plays an important role in the pathogenesis of IBD. In recent years, many studies have identified the critical 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 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) [5–7]. 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 response is initiated and regulated by the interplay between the immune and nonimmune cells [8–10]. 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 cell-mediated humoral immunity are two types of adoptive immunity. The generation of neutralizing antibodies by B lymphocytes is 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 infection. CD4⁺ helper T cells have been found to play critical roles in this progress [13–15]. 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 key mediator in regulating humoral immune response via direct interactions with B cells [16–18]. 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 the production of IL-21 [19–21].

Tfh cell differentiation is a complex and multistage process (Figure 1). Initially, 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 stimulation 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 [22–24]. Tfh cell differentiation is regulated by various factors such as extracellular cytokines, cell-surface molecule interactions, multiple transcription factors, and microRNAs [25, 26].

2.1. Cytokines

2.1.1. IL-6

Cytokine signaling play a critical role in driving naive CD4⁺ T cells to differentiate into distinct effector T cell subsets. Numerous studies have reported the important role IL-6 in regulating Tfh cell differentiation [27]. IL-6 can promote Bcl-6 expression and Tfh cell differentiation by regulating signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling pathway [28]. The deficiency of IL-6 led to delayed Tfh cell formation [29].

2.1.2. IL-21

IL-21 has many regulatory effects on innate and adaptive immune responses [30]. IL-21 can drive Tfh cell differentiation via the STAT3 signaling pathway. IL-21 deficiency in mice resulted in a decreased number of Tfh cells after protein immunization [18]. Besides, Tfh cells can produce IL-21, and IL-21 was necessary for GC formation [31]. IL-21 was also critical in regulation of human B cell differentiation into Ig-secreting cells [32].

2.2. Cell-Surface Factors

2.2.1. CXCR5

CXC chemokine receptor 5 (CXCR5) is an important Tfh cell surface marker. CXCR5 is responsible for the migration of T cells to the B cell zone and thereby lead to T : B cell interaction. By upregulation CXCR5 and downregulation of CCR7, these CD4⁺ T cells migrate to B cell follicles where CXCL13 is expressed, interact with B cells for further maturation, and provide help for B cell activation and GC reactions [33, 34]. CXCR5 can also act as an important factor in modulating Tfh cell differentiation. Knockout of CXCR5 resulted in decreased GC number and humoral immune response [35].

2.2.2. CD28

Cell-surface costimulators, which are important for T cell-B cell interaction, are also responsible for Tfh cell development. The CD28-B7 costimulatory signal pathway is critical for Tfh cell differentiation and GC reaction [36, 37]. CD28 signaling positively regulates the differentiation and survival of Tfh cells. The deficiency of CD28 in mice led to absence of Tfh cells and blocking of CD28 signal inhibited expression of Bcl-6 [38].

2.2.3. ICOS

Inducible costimulator (ICOS) is another costimulator which can bind to ICOSL. ICOS is expressed on Tfh cells and is responsible for Tfh cell differentiation. ICOS^–/– and ICOSL^–/– mice exhibited impaired Tfh generation cell and GC formation. Tfh cell generation and GC formation were significantly impaired in ICOS-deficient patients [39]. ICOS was essential to maintain the phenotype of Tfh cells by regulating transcription factor Klf2 [40]. It was reported that the ICOS-PI3K signaling pathway is critical for Tfh differentiation. The ICOS-PI3K signaling pathway resulted in enhanced Bcl-6 expression and Tfh cell differentiation [41].

2.2.4. PD-1

Programmed death 1 (PD-1), a cell surface factor expressed on exhausted T cells, is also expressed on Tfh cells. PD-1 was initially expected to be a negative regulator in Tfh cell differentiation. Mice with impaired PD-1 signaling showed more Tfh cell numbers after protein immunization [42]. PD-L1-PD-1 interaction controls tissue positioning and function of Tfh cells [43]. PD-L1 can also inhibit T follicular regulatory cells (Tfr) differentiation; the number of Tfr is increased in the absence of PD-1 signaling. PD-1 is expressed by Tfr and also involved in regulating Tfr cells functions [44].

2.3. Transcription Factors

2.3.1. Bcl-6

It is well established that Tfh cells comprise a distinct subset of Th cells and possess a unique gene expression profile. A breakthrough discovery in Tfh cells research is the identification of the master transcription factor, B cell lymphoma 6 (Bcl-6). Bcl-6 plays an essential role in development and function of Tfh cells. Tfh cells cannot be generated in the absence of Bcl-6, whereas overexpression of Bcl-6 could restore this defective Tfh cell differentiation [45, 46]. It was reported that Bcl-6 promoted expression of Tfh marks like CXCR5 and PD-1; however, it repressed the expression of genes critical for other T helper lineages, such as T-bet, IFN-γ, ROR-γt, and IL-17. Bcl-6 acted as a repressive transcription factor which can bind to the promoter of Tbx21 and Rorc, encoding T-bet and RoR-γt, and inhibit development of Th1 and Th17 cells, respectively [47].

2.3.2. STATs

Signal transducer and activator of transcription (STAT) pathways have a positive or negative role in Tfh cell differentiation. STAT1, STAT3, and STAT4 can promote Tfh cell development. The deficiency of these STATs led to the reduction of Tfh cells [48–50]. In contrast, STAT5 plays a negative role in Tfh cell development and humoral immunity. Inhibition of the STAT5 signaling pathway resulted in enhanced Bcl-6 expression, Tfh cell differentiation, and GC formation [51, 52].

2.3.3. Blimp-1

B lymphocyte-induced maturation protein 1 (Blimp-1), a transcriptional factor in regulating of terminal B cell differentiation and function, also plays a role in Tfh cell differentiation. Blimp-1 is an antagonist of Bcl-6; thus, Blimp-1 can inhibit Bcl-6 expression and repress Tfh differentiation [53, 54].

2.4. MicroRNAs

Studies also identified the critical role of microRNAs in Tfh cell differentiation. miR-17 approximately 92 family acts as an important factor in Tfh differentiation during viral infection or protein immunization [55]. miR-155 promoted Tfh cell formation and contributes to development of inflammatory disease during chronic low-grade inflammation [56]. However, miR-146a repressed Tfh cell differentiation by regulating the ICOS/ICOSL signaling pathway [57].

3. Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by symptoms such as diarrhea, abdominal pain, and weight loss. Ulcerative colitis (UC) and Crohn’s disease (CD) are the two major subtypes of IBD [58]. IBD is a worldwide health problem with a continually increasing incidence. Although the exact etiology is still not fully understood, it is well-known that personal genetic susceptibility, environment, intestinal microbiota, and immune system all contribute to the pathogenesis of IBD. Among them, deregulation of immune response in the intestinal mucosa acts as a master factor in the etiology of IBD [59]. The local immunity in the intestinal mucosa is critical for microenvironment homeostasis, as intestinal immune system not only maintains protective immunity against invading pathogens but also controls immune tolerance to commensal microbiota. Nevertheless, the dysregulated immune response against self-antigens or commensal microbiota can lead to mucosal inflammation. Immune cells such as macrophages, neutrophils, dendritic cells, T cells, and B cells have been proved having critical roles in regulating mucosal inflammation [60, 61].

4. The Role of Tfh Cells and IL-21 in IBD

The major function of Tfh cells is to help B cells to generate neutralizing antibodies against pathogenic infection, wherein the dysregulated Tfh cell function is also involved in a range of disorders. Tfh cells can perform their functions through IL-21 [62]. In recent years, increasing evidence has implicated that Tfh cells and the related cytokine IL-21 participate in the pathogenesis of IBD.

4.1. The Role of Tfh Cells and IL-21 in Ulcerative Colitis

4.1.1. Tfh Cells in Ulcerative Colitis

Ulcerative colitis (UC), one of the most frequent forms of IBD, is characterized by mucosal inflammation limited to the colon. The clinical symptoms of UC include blood and mucus release, granulation tissue, and petechial hemorrhage [63]. Recently, several studies have reported that Tfh cells have a role in the pathogenesis of UC.

Tfh cells were elevated in UC patients [64–68]. The value of Mayo clinic score, erythrocyte sedimentation rate (ESR), or C-reactive protein (CRP) in UC patients was positively correlated with frequency of circulating Tfh cells [64]. Bcl-6 mRNA and Tfh cells in the germinal center were increased in the UC groups compared with that in the control group [65]. Recent studies further showed that Tfh cells were significantly increased in active UC patients compared with stable remission UC patients and healthy controls. The level of Tfh cells was positively correlated with circulating new memory B cells, plasmablasts, serum IgG, IL-4, IL-21, serum CRP, and Mayo scores [66]. The level of Tfh cells was significantly decreased when active UC patients achieve clinical remission after treatment. Tfh cells can be used as a biomarker in distinguishing active UC from stable remission patients [67]. Another research also found that the number of Tfh cells was significantly increased in colonic tissues from UC patients [68]. These results implicated that Tfh cells are critical regulators in colitis development.

Activated B cells can highly express the CD86, and the CD86⁺ B cells can differentiate into CD38⁺ plasma B cells which can produce antibodies. Dysregulated B cell response is associated with the pathogenesis of IBD [69, 70]. One study found that the percentages of circulating activated B cells (CD86⁺CD19⁺) and plasma B cells (CD38⁺CD19⁺) were both significantly higher in UC patients than in healthy controls. The percentages of activated B cells, plasma B cells, and serum IgG concentration were positively correlated the percentage of Tfh cells. Tfh cells might regulate the development of UC by controlling the B cell function [71].

Tfh cells can also participate in pathogenesis of UC via a B cell-independent manner. One research showed that adoptive transfer of naive CD4⁺ T cells to Rag1^-/- recipients will lead to development of colitis; however, adoptive transfer of naive Bcl6^-/- CD4⁺ T cells into Rag1^-/- recipient cannot induce Tfh cell differentiation and the development of colitis [72].

T follicular regulatory cells (Tfr) are a specific regulatory T cell subgroup expressing CXCR5 and FoxP3. Tfr can inhibit Tfh cell function and thus suppress humoral immunity [73]. The suppression function of Tfr cells was significantly lower in UC patients than in healthy controls [74]. UC patients exhibited significant reductions in circulating Tfr cells. The value of the Mayo clinic score, erythrocyte sedimentation rate (ESR), or C-reactive protein (CRP) in UC patients was negatively correlated with circulating Tfr cells and Tfr/Tfh ratio [64]. The number of Tfr cells was also reduced in the intestinal germinal center of the UC groups compared with that of the control group [65]. Recent studies further showed that circulating Tfr was decreased in active UC patients compared with stable remission UC patients and healthy controls and Tfr was negatively correlated with serum IgG, circulating new memory B cells, plasmablasts, and clinical characteristics [66].

4.1.2. IL-21 in Ulcerative Colitis

The level of IL-21 is elevated in UC patients compared to healthy controls [64, 65, 71, 75]. Serum IL-21 was significantly higher in active UC compared with HC and stable remission UC patients [66]. The percentage of CD3⁺CD8^-IL-21⁺ T cells in peripheral whole blood was significantly elevated in UC patients [76]. There is also a study that reported that the percentage of IL-21-producing CD4⁺ T intestinal lamina propria lymphocytes (T-LPL) was increased in IBD compared with controls [77]. There is a positive correlation between Tfh cells and the level of IL-21 in UC patients [66, 71]. Besides, the value of Mayo clinic score, erythrocyte sedimentation rate (ESR), or C-reactive protein (CRP) in UC patients was positively correlated with serum IL-21 concentration [64]. IL-21 knockout (IL-21KO) mice were resistant to dextran sulphate sodium- (DSS-) induced colitis. Moreover the count of infiltrating Tfh cells and secretion of Tfh-related cytokines were significantly decreased in IL-21KO mice in comparing to WT mice. Blockade of IL-21 by administration of a neutralizing IL-21 antibody decreased the colonic infiltration of Tfh cells and inhibited development of DSS-induced colitis [68]. Anti-IL-21 mAb treatment also ameliorated CD4⁺CD25⁻ T cell adoptive transfer (AdTr) Colitis [78].

IL-21 might be available for tight monitoring of the disease activity of UC. Serum IL-21 was significantly higher in UC patients with unstable remission compared to UC patients with stable remission. Serum IL-21 was also elevated in UC patients with later occurring relapses [79]. Another research also found that a higher IL-21 level might be an increased risk of UC relapse [80].

4.2. The Role of Tfh Cells and IL-21 in Crohn’s Disease

4.2.1. Tfh Cells in Crohn’s Disease

Crohn’s disease (CD) is another form of IBD. Different from UC, the inflammation in CD can occur throughout the entire gastrointestinal tract. The clinical manifestations of CD are characterized by abdominal pain, diarrhea, malnutrition, and weight loss [81]. In recent years, studies have proved the important role of Tfh cells in pathogenesis of CD.

The percentage of circulating Tfh cells in peripheral blood was significantly elevated in CD patients than in controls, and the percentage of circulating Tfh was significantly increased in penetrating CD compared with inflammatory CD or stricturing CD [82]. The number of Tfh cells was increased, and the number of Tfr cells was decreased in the intestinal germinal center of the CD groups compared with that of the control group [65]. Another study also reported that the percentage of IL-21-positive Tfh cells was higher in CD patients than in controls [77]. Tfh cell frequencies in the intestine and peripheral blood were associated with CD activity. CD patients with clinical response to ustekinumab (IL-12 and IL-23 antagonists) had reduced frequencies of circulating Tfh cells in a concentration-dependent manner. Ustekinumab inhibited Tfh cell differentiation in vitro, and ustekinumab therapy can reduce the germinal center activity in CD patients in vivo [83].

4.2.2. IL-21 in Crohn’s Disease

IL-21 and IL-21R were observed in the mucosa and submucosa from healthy controls within normal limits; however, in patients with CD, IL-21 and IL-21R were additional expressed in lymphoid aggregates of muscularis externa. IL-21R was significantly highly expressed in the intestine from patients with CD compared with that in controls [78]. The expression of IL-21 was upregulated in the CD group compared with that in the control group [65, 75, 79].

5. Conclusion

Tfh cells are a novel subset of CD4 T cells which can provide critical help for germinal center (GC) formation and antibody maturation. Because of the critical role of Tfh cells in adaptive immune response, the accurately control of their differentiation and function is very important. There is increasing evidence that dysregulation of Tfh activities is implicated in the pathogenesis of many autoimmune diseases including IBD. Tfh cells and Tfh-related molecules may become a novel therapeutic target in treatment of IBD in future.

Conflicts of Interest

The authors declare no conflict of interest.

Acknowledgments

The work was supported by the National Natural Science Foundation of China (grant number 81871308), Shandong Provincial Natural Science Foundation Project (grant number ZR2019QH002), Shandong Province Higher Educational Youth Scientific Research Innovation Team Program (grant number 2019KJK018), and Shandong Province Higher Educational Science and Technology Program (grant number J18KA259).

References

S. Crotty, “T follicular helper cell differentiation, function, and roles in disease,” Immunity, vol. 41, no. 4, pp. 529–542, 2014.
View at: Publisher Site | Google Scholar
C. G. Vinuesa, M. A. Linterman, D. Yu, and I. C. M. MacLennan, “Follicular helper T cells,” Annual Review of Immunology, vol. 34, no. 1, pp. 335–368, 2016.
View at: Publisher Site | Google Scholar
J. S. Weinstein, E. I. Herman, B. Lainez et al., “T_FH cells progressively differentiate to regulate the germinal center response,” Nature Immunology, vol. 17, no. 10, pp. 1197–1205, 2016.
View at: Publisher Site | Google Scholar
W. Song and J. Craft, “T follicular helper cell heterogeneity: time, space, and function,” Immunological Reviews, vol. 288, no. 1, pp. 85–96, 2019.
View at: Publisher Site | Google Scholar
L. Zhang, D. K. W. Ocansey, L. Liu et al., “Implications of lymphatic alterations in the pathogenesis and treatment of inflammatory bowel disease,” Biomedicine & Pharmacotherapy, vol. 140, p. 111752, 2021.
View at: Publisher Site | Google Scholar
B. Al-Bawardy, R. Shivashankar, and D. D. Proctor, “Novel and emerging therapies for inflammatory bowel disease,” Frontiers in Pharmacology, vol. 12, p. 651415, 2021.
View at: Publisher Site | Google Scholar
C. M. Spiceland and N. Lodhia, “Endoscopy in inflammatory bowel disease: role in diagnosis, management, and treatment,” World Journal of Gastroenterology, vol. 24, no. 35, pp. 4014–4020, 2018.
View at: Publisher Site | Google Scholar
T. Kucharzik, C. Maaser, A. Lügering et al., “Recent understanding of IBD pathogenesis: implications for future therapies,” Inflammatory Bowel Diseases, vol. 12, no. 11, pp. 1068–1083, 2006.
View at: Publisher Site | Google Scholar
A. Geremia, P. Biancheri, P. Allan, G. R. Corazza, and A. Di Sabatino, “Innate and adaptive immunity in inflammatory bowel disease,” Autoimmunity Reviews, vol. 13, no. 1, pp. 3–10, 2014.
View at: Publisher Site | Google Scholar
T. Imam, S. Park, M. H. Kaplan, and M. R. Olson, “Effector T helper cell subsets in inflammatory bowel diseases,” Frontiers in Immunology, vol. 9, article 1212, 2018.
View at: Publisher Site | Google Scholar
S. H. Lee, J. E. Kwon, and M. L. Cho, “Immunological pathogenesis of inflammatory bowel disease,” Intestinal research, vol. 16, no. 1, pp. 26–42, 2018.
View at: Publisher Site | Google Scholar
M. F. Neurath and M. T. Chiriac, “Targeting immune cell wiring in ulcerative colitis,” Immunity, vol. 51, no. 5, pp. 791–793, 2019.
View at: Publisher Site | Google Scholar
M. J. Shlomchik, W. Luo, and F. Weisel, “Linking signaling and selection in the germinal center,” Immunological Reviews, vol. 288, no. 1, pp. 49–63, 2019.
View at: Publisher Site | Google Scholar
I. Papa and C. G. Vinuesa, “Synaptic interactions in germinal centers,” Frontiers in Immunology, vol. 9, p. 1858, 2018.
View at: Publisher Site | Google Scholar
K. A. Read, M. D. Powell, B. K. Sreekumar, and K. J. Oestreich, “In vitro differentiation of effector CD4₊ T helper cell subsets,” Methods in Molecular Biology, vol. 1960, pp. 75–84, 2019.
View at: Google Scholar
D. Breitfeld, L. Ohl, E. Kremmer et al., “Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production,” The Journal of Experimental Medicine, vol. 192, no. 11, pp. 1545–1552, 2000.
View at: Publisher Site | Google Scholar
P. Schaerli, K. Willimann, A. B. Lang, M. Lipp, P. Loetscher, and B. Moser, “CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function,” The Journal of Experimental Medicine, vol. 192, no. 11, pp. 1553–1562, 2000.
View at: Publisher Site | Google Scholar
R. I. Nurieva, Y. Chung, D. Hwang et al., “Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages,” Immunity, vol. 29, no. 1, pp. 138–149, 2008.
View at: Publisher Site | Google Scholar
S. M. Kerfoot, G. Yaari, J. R. Patel et al., “Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone,” Immunity, vol. 34, no. 6, pp. 947–960, 2011.
View at: Publisher Site | Google Scholar
H. Wu, Y. Deng, M. Zhao et al., “Molecular control of follicular helper T cell development and differentiation,” Frontiers in Immunology, vol. 9, p. 2470, 2018.
View at: Publisher Site | Google Scholar
X. Liu, R. I. Nurieva, and C. Dong, “Transcriptional regulation of follicular T-helper (Tfh) cells,” Immunological Reviews, vol. 252, no. 1, pp. 139–145, 2013.
View at: Publisher Site | Google Scholar
J. K. Krishnaswamy, S. Alsén, U. Yrlid, S. C. Eisenbarth, and A. Williams, “Determination of T follicular helper cell fate by dendritic cells,” Frontiers in Immunology, vol. 9, p. 2169, 2018.
View at: Publisher Site | Google Scholar
X. Zou, G. Sun, F. Huo, L. Chang, and W. Yang, “The role of dendritic cells in the differentiation of T follicular helper cells,” Journal of Immunology Research, vol. 2018, Article ID 7281453, 7 pages, 2018.
View at: Publisher Site | Google Scholar
M. Stebegg, S. D. Kumar, A. Silva-Cayetano, V. R. Fonseca, M. A. Linterman, and L. Graca, “Regulation of the germinal center response,” Frontiers in Immunology, vol. 9, p. 2469, 2018.
View at: Publisher Site | Google Scholar
S. Wali, A. Sahoo, S. Puri, A. Alekseev, and R. Nurieva, “Insights into the development and regulation of T follicular helper cells,” Cytokine, vol. 87, pp. 9–19, 2016.
View at: Publisher Site | Google Scholar
W. Ise, “Development and function of follicular helper T cells,” Bioscience, Biotechnology, and Biochemistry, vol. 80, no. 1, pp. 1–6, 2016.
View at: Publisher Site | Google Scholar
M. A. Linterman and C. G. Vinuesa, “Signals that influence T follicular helper cell differentiation and function,” Seminars in Immunopathology, vol. 32, no. 2, pp. 183–196, 2010.
View at: Publisher Site | Google Scholar
Y. S. Choi, D. Eto, J. A. Yang, C. Lao, and S. Crotty, “Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation,” Journal of Immunology, vol. 190, no. 7, pp. 3049–3053, 2013.
View at: Publisher Site | Google Scholar
A. Karnowski, S. Chevrier, G. T. Belz et al., “B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1,” The Journal of Experimental Medicine, vol. 209, no. 11, pp. 2049–2064, 2012.
View at: Publisher Site | Google Scholar
T. Gharibi, J. Majidi, T. Kazemi, R. Dehghanzadeh, M. Motallebnezhad, and Z. Babaloo, “Biological effects of IL-21 on different immune cells and its role in autoimmune diseases,” Immunobiology, vol. 221, no. 2, pp. 357–367, 2016.
View at: Publisher Site | Google Scholar
A. Vogelzang, H. M. McGuire, D. Yu, J. Sprent, C. R. Mackay, and C. King, “A fundamental role for interleukin-21 in the generation of T follicular helper cells,” Immunity, vol. 29, no. 1, pp. 127–137, 2008.
View at: Publisher Site | Google Scholar
V. L. Bryant, C. S. Ma, D. T. Avery et al., “Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells,” Journal of Immunology, vol. 179, no. 12, pp. 8180–8190, 2007.
View at: Publisher Site | Google Scholar
B. Moser, P. Schaerli, and P. Loetscher, “CXCR5⁺ T cells: follicular homing takes center stage in T-helper-cell responses,” Trends in Immunology, vol. 23, no. 5, pp. 250–254, 2002.
View at: Publisher Site | Google Scholar
S. Hardtke, L. Ohl, and R. Förster, “Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help,” Blood, vol. 106, no. 6, pp. 1924–1931, 2005.
View at: Publisher Site | Google Scholar
C. N. Arnold, D. J. Campbell, M. Lipp, and E. . C. Butcher, “The germinal center response is impaired in the absence of T cell-expressed CXCR5,” European Journal of Immunology, vol. 37, no. 1, pp. 100–109, 2007.
View at: Publisher Site | Google Scholar
M. A. Linterman, A. E. Denton, D. P. Divekar et al., “CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection,” eLife, vol. 3, article e03180, 2014.
View at: Publisher Site | Google Scholar
S. E. Ferguson, S. Han, G. Kelsoe, and C. B. Thompson, “CD28 is required for germinal center formation,” Journal of Immunology, vol. 156, no. 12, pp. 4576–4581, 1996.
View at: Google Scholar
S. Salek-Ardakani, Y. S. Choi, M. Rafii-el-Idrissi Benhnia et al., “B cell-specific expression of B7-2 is required for follicular Th cell function in response to vaccinia virus,” Journal of Immunology, vol. 186, no. 9, pp. 5294–5303, 2011.
View at: Publisher Site | Google Scholar
L. Bossaller, J. Burger, R. Draeger et al., “ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells,” Journal of Immunology, vol. 177, no. 7, pp. 4927–4932, 2006.
View at: Publisher Site | Google Scholar
J. P. Weber, F. Fuhrmann, R. K. Feist et al., “ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2,” The Journal of Experimental Medicine, vol. 212, no. 2, pp. 217–233, 2015.
View at: Publisher Site | Google Scholar
S. Preite, B. Huang, J. L. Cannons, D. B. McGavern, and P. L. Schwartzberg, “PI3K orchestrates T follicular helper cell differentiation in a context dependent manner: implications for autoimmunity,” Frontiers in Immunology, vol. 9, p. 3079, 2019.
View at: Publisher Site | Google Scholar
P. T. Sage, F. A. Schildberg, R. A. Sobel, V. K. Kuchroo, G. J. Freeman, and A. H. Sharpe, “Dendritic cell PD-L1 limits autoimmunity and follicular T cell differentiation and function,” Journal of Immunology, vol. 200, no. 8, pp. 2592–2602, 2018.
View at: Publisher Site | Google Scholar
J. Shi, S. Hou, Q. Fang, X. Liu, X. Liu, and H. Qi, “PD-1 controls follicular T helper cell positioning and function,” Immunity, vol. 49, no. 2, pp. 264–274.e4, 2018.
View at: Publisher Site | Google Scholar
P. T. Sage, L. M. Francisco, C. V. Carman, and A. H. Sharpe, “The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood,” Nature Immunology, vol. 14, no. 2, pp. 152–161, 2013.
View at: Publisher Site | Google Scholar
R. I. Nurieva, Y. Chung, G. J. Martinez et al., “Bcl6 mediates the development of T follicular helper cells,” Science, vol. 325, no. 5943, pp. 1001–1005, 2009.
View at: Publisher Site | Google Scholar
X. Liu, X. Yan, B. Zhong et al., “Bcl6 expression specifies the T follicular helper cell program in vivo,” The Journal of Experimental Medicine, vol. 209, no. 10, pp. 1841–1852, 2012, S1-24.
View at: Publisher Site | Google Scholar
D. Yu, S. Rao, L. M. Tsai et al., “The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment,” Immunity, vol. 31, no. 3, pp. 457–468, 2009.
View at: Publisher Site | Google Scholar
L. S. Ji, X. H. Sun, X. Zhang et al., “Mechanism of follicular helper T cell differentiation regulated by transcription factors,” Journal of Immunology Research, vol. 2020, Article ID 1826587, 9 pages, 2020.
View at: Publisher Site | Google Scholar
C. S. Ma, D. T. Avery, A. Chan et al., “Functional STAT3 deficiency compromises the generation of human T follicular helper cells,” Blood, vol. 119, no. 17, pp. 3997–4008, 2012.
View at: Publisher Site | Google Scholar
J. S. Weinstein, B. J. Laidlaw, Y. Lu et al., “STAT4 and T-bet control follicular helper T cell development in viral infections,” The Journal of Experimental Medicine, vol. 215, no. 1, pp. 337–355, 2018.
View at: Publisher Site | Google Scholar
R. J. Johnston, Y. S. Choi, J. A. Diamond, J. A. Yang, and S. Crotty, “STAT5 is a potent negative regulator of TFH cell differentiation,” The Journal of Experimental Medicine, vol. 209, no. 2, pp. 243–250, 2012.
View at: Publisher Site | Google Scholar
R. I. Nurieva, A. Podd, Y. Chen et al., “STAT5 Protein Negatively Regulates T Follicular Helper (Tfh) Cell Generation and Function,” The Journal of Biological Chemistry, vol. 287, no. 14, pp. 11234–11239, 2012.
View at: Publisher Site | Google Scholar
R. J. Johnston, A. C. Poholek, D. DiToro et al., “Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation,” Science, vol. 325, no. 5943, pp. 1006–1010, 2009.
View at: Publisher Site | Google Scholar
S. Crotty, R. J. Johnston, and S. P. Schoenberger, “Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation,” Nature Immunology, vol. 11, no. 2, pp. 114–120, 2010.
View at: Publisher Site | Google Scholar
T. Wu, A. Wieland, J. Lee et al., “Cutting edge: miR-17-92 is required for both CD4 Th1 and T follicular helper cell responses during viral infection,” Journal of Immunology, vol. 195, no. 6, pp. 2515–2519, 2015.
View at: Publisher Site | Google Scholar
R. Hu, D. A. Kagele, T. B. Huffaker et al., “miR-155 Promotes T Follicular Helper Cell Accumulation during Chronic, Low- Grade Inflammation,” Immunity, vol. 41, no. 4, pp. 605–619, 2014.
View at: Publisher Site | Google Scholar
A. Pratama, M. Srivastava, N. J. Williams et al., “MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres,” Nature Communications, vol. 6, no. 1, p. 6436, 2015.
View at: Publisher Site | Google Scholar
H. Herfarth and G. Rogler, “Endoscopy,” Inflammatory Bowel Disease, vol. 37, no. 1, pp. 42–47, 2005.
View at: Google Scholar
M. Zhao and J. Burisch, “Impact of genes and the environment on the pathogenesis and disease course of inflammatory bowel disease,” Digestive Diseases and Sciences, vol. 64, no. 7, pp. 1759–1769, 2019.
View at: Publisher Site | Google Scholar
M. Parkes, “Evidence from genetics for a role of autophagy and innate immunity in IBD pathogenesis,” Digestive Diseases, vol. 30, no. 4, pp. 330–333, 2012.
View at: Publisher Site | Google Scholar
R. Hodson, “Inflammatory bowel disease,” Nature, vol. 540, no. 7634, p. S97, 2016.
View at: Publisher Site | Google Scholar
N. Gensous, M. Charrier, D. Duluc et al., “T follicular helper cells in autoimmune disorders,” Frontiers in Immunology, vol. 9, p. 1637, 2018.
View at: Publisher Site | Google Scholar
W. Fries and S. Comunale, “Ulcerative colitis: pathogenesis,” Current Drug Targets, vol. 12, no. 10, pp. 1373–1382, 2011.
View at: Publisher Site | Google Scholar
X. Wang, Y. Zhu, M. Zhang et al., “The shifted balance between circulating follicular regulatory T cells and follicular helper T cells in patients with ulcerative colitis,” Clinical Science, vol. 131, no. 24, pp. 2933–2945, 2017.
View at: Publisher Site | Google Scholar
Y. Yang, X. Lv, L. Zhan et al., “Case report: IL-21 and Bcl-6 regulate the proliferation and secretion of Tfh and Tfr cells in the intestinal germinal center of patients with inflammatory bowel disease,” Frontiers in Pharmacology, vol. 11, p. 587445, 2021.
View at: Publisher Site | Google Scholar
Y. Long, C. Xia, L. Xu et al., “The imbalance of circulating follicular helper T cells and follicular regulatory T cells is associated with disease activity in patients with ulcerative colitis,” Frontiers in Immunology, vol. 11, p. 104, 2020.
View at: Publisher Site | Google Scholar
Y. Long, X. Zhao, C. Liu, C. Xia, and C. Liu, “Activated inducible co-stimulator-positive programmed cell death 1-positive follicular helper T cells indicate disease activity and severity in ulcerative colitis patients,” Clinical and Experimental Immunology, vol. 202, no. 1, pp. 106–118, 2020.
View at: Publisher Site | Google Scholar
J. Yu, S. He, P. Liu et al., “Interleukin-21 promotes the development of ulcerative colitis and regulates the proliferation and secretion of follicular T helper cells in the colitides microenvironment,” Molecular Medicine Reports, vol. 11, no. 2, pp. 1049–1056, 2015.
View at: Publisher Site | Google Scholar
K. Pieper, B. Grimbacher, and H. Eibel, “B-cell biology and development,” The Journal of Allergy and Clinical Immunology, vol. 131, no. 4, pp. 959–971, 2013.
View at: Publisher Site | Google Scholar
X. Wang, Y. Jiang, Y. Zhu et al., “Circulating memory B cells and plasmablasts are associated with the levels of serum immunoglobulin in patients with ulcerative colitis,” Journal of Cellular and Molecular Medicine, vol. 20, no. 5, pp. 804–814, 2016.
View at: Publisher Site | Google Scholar
G. Xue, Y. Zhong, L. Hua et al., “Aberrant alteration of follicular T helper cells in ulcerative colitis patients and its correlations with interleukin-21 and B cell subsets,” Medicine, vol. 98, no. 10, article e14757, 2019.
View at: Publisher Site | Google Scholar
R. Zhang, C.-f. Qi, Y. Hu et al., “T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation,” Journal of Autoimmunity, vol. 96, pp. 113–122, 2019.
View at: Publisher Site | Google Scholar
P. T. Sage and A. H. Sharpe, “The multifaceted functions of follicular regulatory T cells,” Current Opinion in Immunology, vol. 67, pp. 68–74, 2020.
View at: Publisher Site | Google Scholar
S. Wang, T. Fan, L. Yao, R. Ma, S. Yang, and F. Yuan, “Circulating follicular regulatory T cells could inhibit Ig production in a CTLA-4-dependent manner but are dysregulated in ulcerative colitis,” Molecular Immunology, vol. 114, pp. 323–329, 2019.
View at: Publisher Site | Google Scholar
Z. H. Nemeth, D. A. Bogdanovski, P. Barratt-Stopper, S. R. Paglinco, L. Antonioli, and R. H. Rolandelli, “Crohn's disease and ulcerative colitis show unique cytokine profiles,” Cureus, vol. 9, no. 4, article e1177, 2017.
View at: Publisher Site | Google Scholar
J. Ge, X. Zhang, J. Liu et al., “Elevated expression of interleukin-21 and its correlation to T-cell subpopulation in patients with ulcerative colitis,” Central European Journal of Immunology, vol. 40, no. 3, pp. 331–336, 2015.
View at: Publisher Site | Google Scholar
M. Sarra, I. Monteleone, C. Stolfi et al., “Interferon-gamma-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases,” Inflammatory Bowel Diseases, vol. 16, no. 8, pp. 1332–1339, 2010.
View at: Publisher Site | Google Scholar
T. L. Holm, D. Tornehave, H. Søndergaard et al., “Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease,” Gastroenterology Research and Practice, vol. 2018, Article ID 5962624, 22 pages, 2018.
View at: Publisher Site | Google Scholar
C. Kessel, M. Lavric, T. Weinhage et al., “Serum biomarkers confirming stable remission in inflammatory bowel disease,” Scientific Reports, vol. 11, no. 1, p. 6690, 2021.
View at: Publisher Site | Google Scholar
K. Fukaura, Y. Iboshi, H. Ogino et al., “Mucosal profiles of immune molecules related to T helper and regulatory T cells predict future relapse in patients with quiescent ulcerative colitis,” Inflammatory Bowel Diseases, vol. 25, no. 6, pp. 1019–1027, 2019.
View at: Publisher Site | Google Scholar
D. C. Baumgart and W. J. Sandborn, “Crohn's disease,” The Lancet, vol. 380, no. 9853, pp. 1590–1605, 2012.
View at: Publisher Site | Google Scholar
Z. Wang, Z. Wang, Y. Diao, X. Qian, N. Zhu, and W. Dong, “Circulating follicular helper T cells in Crohn's disease (CD) and CD-associated colorectal cancer,” Tumour Biology, vol. 35, no. 9, pp. 9355–9359, 2014.
View at: Publisher Site | Google Scholar
A.-M. Globig, N. P. Sommer, K. Wild et al., “Ustekinumab inhibits T follicular helper cell differentiation in patients with Crohn's disease,” Cellular and Molecular Gastroenterology and Hepatology, vol. 11, pp. 1–12, 2021.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2021 Lulu Sun et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

866

Downloads

978

Citations