IL-21 Contributes to Fatal Inflammatory Disease in the Absence of Foxp3+ T Regulatory Cells

Vogelzang, Alexis; McGuire, Helen M.; Liu, Sue Min; Gloss, Brian; Mercado, Karessa; Earls, Peter; Dinger, Marcel E.; Batten, Marcel; Sprent, Jonathan; King, Charles M.

doi:10.4049/jimmunol.1302285

Cited by 16 publications

(14 citation statements)

References 47 publications

(34 reference statements)

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“…IL-21 exerts its effect on a broad range of cell types. Increasing evidence shows that IL-21 potently regulates innate and adaptive immune response (6)(7)(8). Furthermore, the role of IL-21 in angiogenesis has also been studied (9,10).…”

Section: Introductionmentioning

confidence: 99%

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Yuan

Wang

2016

Biomedical Reports

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Abstract. and its receptor (IL-21R) are broadly expressed on human B cells, activated T cells and other myeloid cells. IL-21 cooperates with IL-6 and transforming growth factor-β to regulate T-cell differentiation. IL-21-mediated human B cell and dendritic cells differentiation requires signal transducer and activator of transcription 3 (STAT3), and also induces B-cell apoptosis dependents on the Toll-like receptor signal. Recently, in vitro and in vivo experiments showed that IL-21/IL-21R regulate angiogenesis through STAT3. IL-21 signaling pathways are complex due to its cooperation with other transcriptional factors, such as interferon regulatory factor 4 and granulocyte-macrophage colony-stimulating factor. The Janus kinase-STAT pathway has been the most extensively studied. With the increase in the understanding of IL-21 biology in the context of each specific disease or pathological condition, IL-21 could be a new therapeutic target for immune-related disease.

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Section: Introductionmentioning

confidence: 99%

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Yuan

Wang

2016

Biomedical Reports

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“…11 Furthermore, it is perceived that IL-21 has the ability to augment the Th17 response by means of a positive feedback loop as Th17 cells are one of the most prominent producers of IL-21. 11,12 The loss of expression of the IL-21 or the IL21R causes a deficient Th17 response in vitro, which further supports IL-21 involvement in Th17 cell differentiation. 11,43,52,53 Additionally in vivo, IL-21 has been shown to significantly influence the differentiation of the Th17 subset during the development of experimental autoimmune encephalomyelitis (EAE).…”

Section: Discussionmentioning

confidence: 70%

“…11 It is believed that IL-21 has the ability to augment the Th17 response by means of a positive feedback loop, as Th17 cells are one of the most prominent producers of IL-21. 11,12 The relationship between IL-21 and acute pancreatitis (AP) is unknown. AP is an inflammatory condition of the pancreas, as a result of various aetiologies, that initiates a varied systemic inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Transient Expression of Interleukin-21 in the Second Hit of Acute Pancreatitis May Potentiate Immune Paresis in Severe Acute Pancreatitis

Thomson

Nweke

Brand³

et al. 2019

Pancreas

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Objectives: Interleukin (IL)-21 is a cytokine associated with tissue inflammation, autoimmune and infectious diseases. Organ dysfunction and death can occur in patients with acute pancreatitis in two distinct clinical phases. Initially, a systemic inflammatory response syndrome which may be followed by systemic sepsis from infected pancreatic necrosis, known as the 'second hit'. The expression and possible role of IL-21 in acute pancreatitis has not been established. Methods: Thirty-six patients with mild, moderate and severe acute pancreatitis were enrolled. Peripheral blood samples of patients were drawn on days 7, 9, 11, and 13. Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were performed to determine the expression and concentration of IL-21. Results: Interleukin-21 mRNA levels increased significantly at day 9 in severe (P = 0.002) pancreatitis compared to both the mild and control patient groups. At the protein level, IL-21 was elevated in severe acute pancreatitis patients compared to mild, although this was not significant. Furthermore, day 9 IL-21 was elevated in septic severe acute pancreatitis patients and patients with pancreatic necrosis. Conclusions: Interleukin-21 is transiently elevated in severe acute pancreatitis compared to the mild/moderate group and hence IL-21 may contribute to the immune imbalance that occurs in acute pancreatitis.

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“…Therefore, we examined CCR9 +/− Th and CCR9 +/− Tfh cells in two models of autoimmunity and inflammation, namely the NOD mouse and mice that have been made genetically deficient in IL-2 ( Il2 −/− mice). NOD mice exhibit a mild subclinical colitis (28), whereas Il2 −/− mice that lack IL-2 dependent Tregs and exhibit multi-organ autoimmunity, exhibit a chronically inflamed GIT (29). The GIT inflammation in Il2 −/− mice is influenced by microbiotia as colitis is significantly reduced under germ-free conditions (30).…”

Section: Resultsmentioning

confidence: 99%

CCR9 Expressing T Helper and T Follicular Helper Cells Exhibit Site-Specific Identities During Inflammatory Disease

et al. 2019

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CD4+ T helper (Th) cells that express the gut homing chemokine receptor CCR9 are increased in the peripheral blood of patients with inflammatory bowel disease and Sjögren's syndrome and in the inflamed lesions of autoimmune diseases that affect the accessory organs of the digestive system. However, despite the important role of the GIT in both immunity and autoimmunity, the nature of CCR9-expressing cells in GIT lymphoid organs and their role in chronic inflammatory diseases remains unknown. In this study, we analyzed the characteristics of CCR9+ Th and T follicular helper (Tfh) cells in GIT associated lymphoid tissues in health, chronic inflammation and autoimmunity. Our findings reveal an association between the transcriptome and phenotype of CCR9+ Th in the pancreas and CCR9+ Tfh cells from GIT-associated lymphoid tissues. GIT CCR9+ Tfh cells exhibited characteristics, including a Th17-like transcriptome and production of effector cytokines, which indicated a microenvironment-specific signature. Both CCR9+ Tfh cells and CCR9+ Th cells from GIT-associated lymphoid tissues migrated to the pancreas. The expression of CCR9 was important for migration of both subsets to the pancreas, but Tfh cells that accumulated in the pancreas had downmodulated expression of CXCR5. Taken together, the findings provide evidence that CCR9+ Tfh cells and Th cells from the GIT exhibit plasticity and can accumulate in distal accessory organs of the digestive system where they may participate in autoimmunity.

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IL-21 Contributes to Fatal Inflammatory Disease in the Absence of Foxp3+ T Regulatory Cells

Cited by 16 publications

References 47 publications

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Transient Expression of Interleukin-21 in the Second Hit of Acute Pancreatitis May Potentiate Immune Paresis in Severe Acute Pancreatitis

CCR9 Expressing T Helper and T Follicular Helper Cells Exhibit Site-Specific Identities During Inflammatory Disease

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