scholarly journals IL-17A and Th17 Cells in Lung Inflammation: An Update on the Role of Th17 Cell Differentiation and IL-17R Signaling in Host Defense against Infection

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Hsing-Chuan Tsai ◽  
Sharlene Velichko ◽  
Li-Yin Hung ◽  
Reen Wu
Keyword(s):  
Cell Differentiation ◽  
Host Defense ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Critical Role ◽  
Klebsiella Pneumonia ◽  
Antimicrobial Proteins ◽  
Cytokines And Chemokines ◽  
Th17 Cell Differentiation

The significance of Th17 cells and interleukin- (IL-)17A signaling in host defense and disease development has been demonstrated in various infection and autoimmune models. Numerous studies have indicated that Th17 cells and its signature cytokine IL-17A are critical to the airway’s immune response against various bacteria and fungal infection. Cytokines such as IL-23, which are involved in Th17 differentiation, play a critical role in controllingKlebsiella pneumonia(K. pneumonia) infection. IL-17A acts on nonimmune cells in infected tissues to strengthen innate immunity by inducing the expression of antimicrobial proteins, cytokines, and chemokines. Mice deficient in IL-17 receptor (IL-17R) expression are susceptible to infection by various pathogens. In this review, we summarize the recent advances in unraveling the mechanism behind Th17 cell differentiation, IL-17A/IL-17R signaling, and also the importance of IL-17A in pulmonary infection.

scholarly journals Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

2009 ◽  
Vol 206 (11) ◽  
pp. 2407-2416 ◽  
Author(s):  
Jyoti Das ◽  
Guangwen Ren ◽  
Liying Zhang ◽  
Arthur I. Roberts ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Th2 Cells ◽  
Th17 Cell Differentiation ◽  
Th1 And Th2

Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor γt, a Th17-specific transcription factor. Interestingly, in Stat-6−/−T-bet−/− mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6−/−T-bet−/− mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.

scholarly journals RORα enforces stability of the T-helper-17 cell effector program

2020 ◽  
Author(s):  
June-Yong Lee ◽  
Jason A. Hall ◽  
Maria Pokrovskii ◽  
Lina Kroehling ◽  
Lin Wu ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Helper ◽  
T Helper 17 ◽  
Enhancer Element ◽  
Peripheral Tissues ◽  
Th17 Cell Differentiation

SummaryT helper 17 (Th17) cells regulate mucosal barrier defenses, but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been described, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation, but a distinct role of the closely-related RORα, which is co-expressed in Th17 cells, is not known. Here we demonstrate that, although dispensable for Th17 cell differentiation, RORα governs optimal Th17 responses in peripheral tissues. Thus, the absence of RORα in T cells led to significant reductions in both RORγt expression and effector function amongst Th17 cells, due to need for cooperative RORα and RORγt binding to a newly-identified Rorc enhancer element that is essential for Th17 lineage maintenance in vivo. Altogether, these data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program.

Antrodia cinnamomea Extract Inhibits Th17 Cell Differentiation and Ameliorates Imiquimod-Induced Psoriasiform Skin Inflammation

2015 ◽  
Vol 43 (07) ◽  
pp. 1401-1417 ◽  
Author(s):  
Ming-Han Li ◽  
Hsin-Chieh Wu ◽  
Hsin-Jan Yao ◽  
Chi-Chen Lin ◽  
Shu-Fang Wen ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Critical Role ◽  
Skin Inflammation ◽  
Therapeutic Effects ◽  
Antrodia Cinnamomea ◽  
Th17 Cell Differentiation ◽  
Stat3 Phosphorylation

Antrodia cinnamomea (A. cinnamomea) is a Chinese medicinal herb that possesses a broad range of bioactivities, including anti-inflammation. Given that the proinflammatory cytokine IL-17 plays a critical role in the pathogenesis of autoimmune diseases, we investigated whether A. cinnamomea could inhibit the development of Th17 cells, the main producer of IL-17, and exhibit therapeutic effects on an animal model of psoriasis. We found that A. cinnamomea extract (AC) inhibited the differentiation of Th17 cells as well as the production of IL-17A, IL-21, and IL-22 from these cells. This effect was associated with the inhibition of STAT3 phosphorylation and ROR[Formula: see text]t expression. Notably, the oral administration of AC reduced psoriasis-like inflammation in imiquimod-mediated dermal damage, repressed the expression of IL-17A, IL-22, and TNF-[Formula: see text] in skin lesions, and decreased the infiltration of CD4[Formula: see text] T cells, CD8[Formula: see text] T cells, and neutrophils into the dermis. Finally, serum levels of IL-17A were decreased in AC-treated mice with psoriasis-like skin inflammation. Taken together, these findings indicate that AC inhibits Th17 cell differentiation, suggesting a role for A. cinnamomea in the treatment of psoriasis and other Th17 cell-mediated inflammatory diseases.

scholarly journals Mapping Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells

2021 ◽  
Author(s):  
Ankitha Shetty ◽  
Santosh D. Bhosale ◽  
Subhash Kumar Tripathi ◽  
Tanja Buchacher ◽  
Rahul Biradar ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Affinity Purification ◽  
Mass Spectrometry Analysis ◽  
Binding Partners ◽  
Th17 Cell Differentiation

Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell-differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among these, FOSL1 and FOSL2 influence the effector responses of Th17 cells. However, the molecular mechanisms underlying their functions are unclear, owing to the poorly characterized protein interaction networks of these factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification–mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a major fraction of these interactors to be associated with RNA binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17-fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL1 and FOSL2 that potentially govern Th17 cell-differentiation and associated pathologies.

The role of metabolism in Th17 cell differentiation and autoimmune diseases

2022 ◽  
Vol 103 ◽  
pp. 108450
Author(s):  
Guang Wang ◽  
Zehong Su ◽  
Hui Li ◽  
Li Xiao ◽  
Chengyue Li ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Autoimmune Diseases ◽  
Th17 Cell ◽  
Th17 Cell Differentiation

scholarly journals BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation

2018 ◽  
Vol 215 (9) ◽  
pp. 2413-2428 ◽  
Author(s):  
Krystin Deason ◽  
Ty Dale Troutman ◽  
Aakanksha Jain ◽  
Dilip K. Challa ◽  
Rajakumar Mandraju ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Activated T Cells ◽  
Th1 Cell ◽  
Th17 Cell Differentiation ◽  
Th 17 ◽  
Phosphoinositide 3 Kinase

The toll-like receptor (TLR) and interleukin (IL)–1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll–IL-1 receptor homology domain–containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R–induced phosphoinositide 3-kinase–Akt–mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β–induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.

Malignant B Cells Skew the Balance between Treg Cell and TH17 Cell Differentiation in B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1347-1347
Author(s):  
Zhi-Zhang Yang ◽  
Anne J. Novak ◽  
Thomas E. Witzig ◽  
Stephen M. Ansell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Th17 Cell Differentiation

Abstract Numerous clinical therapies have attempted to modulate tumor cell immunity, but for the most part, have proven unsuccessful. The inability to produce or augment an effective immune response is due in part to regulatory T (Treg) cells, which inhibit CD4 and CD8 T cell function. Our group has recently shown that Treg cell numbers are elevated in NHL tumors and that NHL B cells induce the development of Treg cells thereby inhibiting anti-tumor responses. The ability of NHL B cells to direct the cellular composition of their microenvironment is critical to our understanding of tumor immunity and we therefore wanted to determine if NHL B cells also directed the expansion or reduction of other T cell populations. IL-17-secreting CD4+ T cells (TH17), a newly characterized CD4+ T helper cell lineage, promote inflammation and play an important role in autoimmune disease. IL-17 has been shown to inhibit tumor cell growth suggesting a potential role for TH17 cells in anti-tumor immunity. We therefore set out to determine if TH17 cells were present in NHL tumors and whether or not their numbers were regulated by NHL B cells. Using unsorted mononuclear cells from malignant lymph nodes, we were unable to detect IL-17 expression in resting CD4+ T cells or CD4+ T cells activated with PMA/Ionomycin stimulation (less than 1%). However, IL-17-secreting CD4+ T cells could be detected in significant numbers in inflammatory tonsil and normal PBMCs. Interestingly, depletion of CD19+ NHL B cells from mononuclear cells obtained from patient biopsies resulted in detection of a clear population of IL-17-secreting CD4+ T cells (5%). These results suggest that NHL B cells suppress TH17 cell differentiation. The frequency of IL-17-secreting CD4+ T cells could not be further enhanced by the addition of exogenous TGF-b and IL-6, a cytokine combination favoring for TH17 differentiation, suggesting a further impairment of TH17 cell differentiation in the tumor microenvironment. In contrast, Foxp3 expression could be detected in resting CD4+ T cells (30%) and could be induced in CD4+CD25−Foxp3− T cells activated with TCR stimulation (28%). Contrary to the inhibition of TGF-b-mediated TH17 differentiation, Foxp3 expression could be dramatically upregulated by TGF-b in intratumoral CD4+ T cells (35%). In addition, lymphoma B cells strongly enhanced Foxp3 expression in intratumoral CD4+CD25−Foxp3−. Furthermore, when added together, the frequency of Foxp3+ T cells and Foxp3-inducible cells reached up to 60% of CD4+ T cells in tumor microenvironment of B-cell NHL. These findings suggest that the balance of effector TH17 cells and inhibitory Treg cells is disrupted in B-cell NHL and significantly favors the development of inhibitory Treg cells. Our data indicate that lymphoma B cells are key factor in regulating differentiation of intratumoral CD4+ T cells toward inhibitory CD4+ T cells.

Sign in / Sign up

Export Citation Format

Share Document