Tumor exosome promotes Th17 cell differentiation by transmitting the lncRNA CRNDE-h in colorectal cancer

AbstractThe T helper 17 (Th17) cells in tumor microenvironment play an important role in colorectal cancer (CRC) progression. This study investigated the mechanism of Th17 cell differentiation in CRC with a focus on the role of tumor exosome-transmitted long noncoding RNA (lncRNA). Exosomes were isolated from the CRC cells and serum of CRC patients. The role and mechanism of the lncRNA CRNDE-h transmitted by CRC exosomes in Th17 cell differentiation were assessed by using various molecular biological methods. The serum exosomal CRNDE-h level was positively correlated with the proportion of Th17 cells in the tumor-infiltrating T cells in CRC patients. CRC exosomes contained abundant CRNDE-h and transmitted them to CD4+ T cells to increase the Th17 cell proportion, RORγt expression, and IL-17 promoter activity. The underlying mechanism is that, CRNDE-h bound to the PPXY motif of RORγt and impeded the ubiquitination and degradation of RORγt by inhibiting its binding with the E3 ubiquitin ligase Itch. The in vivo experiments confirmed that the targeted silence of CRNDE-h in CD4+ T cells attenuated the CRC tumor growth in mice. The present findings demonstrated that the tumor exosome transmitted CRNDE-h promoted Th17 cell differentiation by inhibiting the Itch-mediated ubiquitination and degradation of RORγt in CRC, expanding our understanding of Th17 cell differentiation in CRC.

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

10.1101/2020.12.15.422921 ◽

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.

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

Blood ◽

10.1182/blood.v110.11.1347.1347 ◽

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.

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Engineered Th17 cell differentiation using a photo-activatable immune modulator

10.1101/719021 ◽

2019 ◽

Author(s):

Bibudha Parasar ◽

Pamela V. Chang

Keyword(s):

Cell Differentiation ◽

Th17 Cell ◽

Th17 Cells ◽

Uv Light ◽

T Cell Subsets ◽

Light Illumination ◽

Immune Modulator ◽

On Demand ◽

Th17 Cell Differentiation

AbstractT helper 17 (Th17) cells, an important subset of CD4+ T cells, help to eliminate extracellular infectious pathogens that have invaded our tissues. Despite the critical roles of Th17 cells in immunity, how the immune system regulates the production and maintenance of this cell type remains poorly understood. In particular, the plasticity of these cells, or their dynamic ability to trans-differentiate into other CD4+ T cell subsets, remains mostly uncharacterized. Here, we report a synthetic immunology approach using a photo-activatable immune modulator (PIM) to increase Th17 cell differentiation on demand with spatial and temporal precision to help elucidate this important and dynamic process. In this chemical strategy, we developed a latent agonist that, upon photochemical activation, releases a small-molecule ligand that targets the aryl hydrocarbon receptor (AhR) and ultimately induces Th17 cell differentiation. We used this chemical tool to control AhR activation with spatiotemporal precision within cells and to modulate Th17 cell differentiation on demand by using UV light illumination. We envision that this approach will enable an understanding of the dynamic functions and behaviors of Th17 cells in vivo during immune responses and in mouse models of inflammatory disease.

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Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3

Journal of Experimental Medicine ◽

10.1084/jem.20130791 ◽

2014 ◽

Vol 211 (9) ◽

pp. 1857-1874 ◽

Cited By ~ 64

Author(s):

Shigeru Tanaka ◽

Akira Suto ◽

Taro Iwamoto ◽

Daisuke Kashiwakuma ◽

Shin-ichiro Kagami ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

Cd4 T Cells ◽

Th17 Cell ◽

Delayed Type Hypersensitivity ◽

Dependent Manner ◽

Downstream Targets ◽

Th17 Cell Differentiation ◽

Downstream Effectors

Stat3 signaling is essential for the induction of RORγt and subsequent Th17 cell differentiation. However, the downstream targets of Stat3 for RORγt expression remain largely unknown. We show here that a novel isoform of Sox5, named Sox5t, is induced in Th17 cells in a Stat3-dependent manner. In vivo, T cell–specific Sox5-deficient mice exhibit impaired Th17 cell differentiation and are resistant to experimental autoimmune encephalomyelitis and delayed-type hypersensitivity. Retrovirus-mediated induction of Sox5 together with c-Maf induces Th17 cell differentiation even in Stat3-deficient CD4+ T cells but not in RORγt-deficient CD4+ T cells, indicating that Sox5 and c-Maf induce Th17 cell differentiation as downstream effectors of Stat3 and as upstream inducers of RORγt. Moreover, Sox5 physically associates with c-Maf via the HMG domain of Sox5 and DNA-binding domain of c-Maf, and Sox5 together with c-Maf directly activates the promoter of RORγt in CD4+ T cells. Collectively, our results suggest that Sox5 and c-Maf cooperatively induce Th17 cell differentiation via the induction of RORγt as downstream targets of Stat3.

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Correlation of Interleukin-17-Producing Effector Memory T Cells and CD4+CD25+Foxp3 Regulatory T Cells with the Phosphate Levels in Chronic Hemodialysis Patients

The Scientific World JOURNAL ◽

10.1155/2014/593170 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Cheng-Lin Lang ◽

Min-Hui Wang ◽

Kuan-Yu Hung ◽

Sung-Hao Hsu ◽

Chih-Kang Chiang ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

Th17 Cell ◽

Th17 Cells ◽

Treg Cells ◽

Chronic Hemodialysis ◽

T Cell Differentiation ◽

Effector Memory ◽

Interleukin 17 ◽

Th17 Cell Differentiation

Background and Objectives. Hyperparathyroidism and hyperphosphatemia contribute to the inflammatory effects in chronic hemodialysis (HD) patients. Interleukin-17-producingCD4+effector memory T (Th17) cells and CD4+CD25+Foxp3 regulatory T (Treg) cells both play critical roles in immune activation and inflammation. We investigated the relationship between the Treg and Th17 cells and the phosphate level in chronic HD patients.Methods. 105 patients aged ≥35 years on chronic HD over 3 months were enrolled. The peripheral blood mononuclear cells were collected, cultured, and stimulated by phytohemagglutinin-L, phorbol myristate acetate, and ionomycin at different time points for T cell differentiation.Results. The T cell differentiation was as follows: Th17 cells (mean ± standard deviation (SD): 25.61% ± 10.2%) and Treg cells (8.45% ± 4.3%). The Th17 cell differentiation was positively correlated with the phosphate and albumin levels and negatively correlated with age. The Treg cell differentiation was negatively correlated with albumin level and age. In the nondiabetes group (n=53), the Th17 cell differentiation was predominantly correlated with the phosphate and iPTH (intact parathyroid hormone) levels as well as the dialysis vintage.Conclusion. Higher phosphate and iPTH levels and longer dialysis duration may increase Th17 cell differentiation, especially in the nondiabetic chronic HD patients.

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CD147 Is Essential for the Development of Psoriasis via the Induction of Th17 Cell Differentiation

International Journal of Molecular Sciences ◽

10.3390/ijms23010177 ◽

2021 ◽

Vol 23 (1) ◽

pp. 177

Author(s):

Aoi Okubo ◽

Youhei Uchida ◽

Yuko Higashi ◽

Takuya Sato ◽

Youichi Ogawa ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

Cd4 T Cells ◽

Th17 Cell ◽

Th17 Cells ◽

Transmembrane Protein ◽

Immunoglobulin Superfamily ◽

Monocarboxylate Transporters ◽

Th17 Cell Differentiation

Th17 cells play an important role in psoriasis. The differentiation of naïve CD4+ T cells into Th17 cells depends on glycolysis as the energy source. CD147/basigin, an integral transmembrane protein belonging to the immunoglobulin superfamily, regulates glycolysis in association with monocarboxylate transporters (MCTs)-1 and -4 in cancer cells and T cells. We examined whether CD147/basigin is involved in the pathogenesis of psoriasis in humans and psoriasis-model mice. The serum level of CD147 was increased in patients with psoriasis, and the expression of CD147 and MCT-1 was elevated in their dermal CD4+ RORγt+ T cells. In vitro, the potential of naïve CD4+ T cells to differentiate into Th17 cells was abrogated in CD147−/− T cells. Imiquimod (IMQ)-induced psoriatic dermatitis was significantly milder in CD147−/− mice and bone marrow chimeric mice lacking CD147 in the hematopoietic cells of myeloid lineage. These findings demonstrate that CD147 is essential for the development of psoriasis via the induction of Th17 cell differentiation.

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Regulating human Th17 cells via differential expression of IL-1 receptor

Blood ◽

10.1182/blood-2009-08-236521 ◽

2010 ◽

Vol 115 (3) ◽

pp. 530-540 ◽

Cited By ~ 97

Author(s):

Won-Woo Lee ◽

Seong Wook Kang ◽

Jihoon Choi ◽

Seung-Hyun Lee ◽

Kamini Shah ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Differential Expression ◽

Cd4 T Cells ◽

Th17 Cell ◽

Th17 Cells ◽

Receptor Expression ◽

Th17 Cell Differentiation ◽

Memory Cd4 T Cells

Abstract In humans, interleukin-1β (IL-1β) has been suggested as an essential cytokine for developing IL-17– or IL-17A–producing CD4+ T helper 17 (Th17) cells. However, little is known about the relationship of IL-1 receptor expression and Th17 cell differentiation. We report here the presence of 2 distinct CD4+ T-cell populations with and without expression of IL-1RI that correlates with the capacity to produce IL-17 in naive and memory CD4+ T cells of human peripheral blood. IL-1RI+ memory CD4+ T cells had increased gene expression of IL17, RORC, and IRF4 even before T-cell receptor triggering, indicating that the effect of IL-1β is programmed in these cells via IL-1RI. Although CD4+ T cells from umbilical cord blood did not express IL-1RI, the cytokines IL-7, IL-15, and transforming growth factor-β (TGF-β) up-regulated IL-1RI expression on naive CD4+ T cells, suggesting that IL-1RI+ naive CD4+ T cells develop in periphery. Furthermore, IL-17 production from the cytokine-treated naive CD4+ T cells was induced by IL-1β and this induction was blocked by IL-1R antagonist. These results indicate that human Th17 cell differentiation is regulated via differential expression of IL-1RI, which is controlled by IL-7 and IL-15.

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

The American Journal of Chinese Medicine ◽

10.1142/s0192415x15500792 ◽

2015 ◽

Vol 43 (07) ◽

pp. 1401-1417 ◽

Cited By ~ 4

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.

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Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and interleukin-6 production

Blood ◽

10.1182/blood-2009-01-198283 ◽

2009 ◽

Vol 114 (5) ◽

pp. 1005-1015 ◽

Cited By ~ 77

Author(s):

Chongyun Fang ◽

Xinhua Zhang ◽

Takashi Miwa ◽

Wen-Chao Song

Keyword(s):

Cell Differentiation ◽

Th17 Cell ◽

Transfer Model ◽

T Helper ◽

T Helper 17 ◽

C5a Receptor ◽

Serum Factors ◽

Th17 Cell Differentiation

Toll-like receptors (TLRs) and complement are 2 major components of innate immunity that provide a first-line host defense and shape the adaptive immune responses. We show here that coincidental activation of complement and several TLRs in mice led to the synergistic production of serum factors that promoted T-helper cell 17 (Th17) differentiation from anti-CD3/CD28 or antigen-stimulated T cells. Although multiple TLR-triggered cytokines were regulated by complement, Th17 cell–promoting activity in the serum was correlated with interleukin (IL)–6 induction, and antibody neutralization of IL-6 abrogated the complement effect. By using both in vitro and in vivo approaches, we examined in more detail the mechanism and physiologic implication of complement/TLR4 interaction on Th17-cell differentiation. We found that the complement effect required C5a receptor, was evident at physiologically relevant levels of C5a, and could be demonstrated in cultured peritoneal macrophages as well as in the setting of antigen immunization. Importantly, despite an inhibitory effect of complement on IL-23 production, complement-promoted Th17 cells were functionally competent in causing autoimmunity in an adoptive transfer model of experimental autoimmune encephalomyelitis. Collectively, these data establish a link between complement/TLR interaction and Th17-cell differentiation and provide new insight into the mechanism of action of complement in autoimmunity.

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TNFαPromotes Th17 Cell Differentiation through IL-6 and IL-1βProduced by Monocytes in Rheumatoid Arthritis

Journal of Immunology Research ◽

10.1155/2014/385352 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 30

Author(s):

Yingxia Zheng ◽

Lei Sun ◽

Ting Jiang ◽

Dongqing Zhang ◽

Dongyi He ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Cell Differentiation ◽

Th17 Cell ◽

Critical Role ◽

Underlying Mechanism ◽

Expression Level ◽

Dependent Manner ◽

Th17 Cell Differentiation ◽

Stat3 Phosphorylation

TNFαplays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFαaberrantly produced in rheumatoid synovium. Interestingly, TNFαcannot induce IL-17 production of CD4+T cells directly, but through the monocytes high levels of IL-1βand IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFαwas shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4+T cells when cultured with CD14+monocytes. Treatment with an approved TNFαblocking antibody showed marked reduction in the levels of IL-6, IL-1β, and IL-17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFαin the pathogenic Th17 cell differentiation in rheumatoid arthritis.

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