scholarly journals Complement drives Th17 cell differentiation and triggers autoimmune arthritis

2010 ◽  
Vol 207 (6) ◽  
pp. 1135-1143 ◽  
Author(s):  
Motomu Hashimoto ◽  
Keiji Hirota ◽  
Hiroyuki Yoshitomi ◽  
Shinji Maeda ◽  
Shin Teradaira ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Autoimmune Disease ◽  
Complement Activation ◽  
Th17 Cell ◽  
Autoimmune Arthritis ◽  
Serum Complement ◽  
Gm Csf ◽  
Th17 Cell Differentiation

Activation of serum complement triggers Th17 cell–dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or β-glucan, both of which activate serum complement, evoked Th17 cell–mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.e., lectin, classical, and alternative), stimulated tissue-resident macrophages, but not dendritic cells, to produce inflammatory cytokines including IL-6, in synergy with Toll-like receptor signaling or, notably, granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF secreted by activated T cells indeed enhanced in vitro IL-6 production by C5a-stimulated macrophages. In vivo, C5a receptor (C5aR) deficiency in SKG mice inhibited the differentiation/expansion of Th17 cells after mannan or β-glucan treatment, and consequently suppressed the development of arthritis. Transfer of SKG T cells induced Th17 cell differentiation/expansion and produced arthritis in C5aR-sufficient recombination activating gene (RAG)−/− mice but not in C5aR-deficient RAG−/− recipients. In vivo macrophage depletion also inhibited disease development in SKG mice. Collectively, the data suggest that complement activation by exogenous or endogenous stimulation can initiate Th17 cell differentiation and expansion in certain autoimmune diseases and presumably in microbial infections. Blockade of C5aR may thus be beneficial for controlling Th17-mediated inflammation and autoimmune disease.

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

2014 ◽  
Vol 211 (9) ◽  
pp. 1857-1874 ◽  
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.

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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Junfeng Sun ◽  
Haowei Jia ◽  
Xingqi Bao ◽  
Yue Wu ◽  
Tianyu Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
T Helper 17 ◽  
Th17 Cell Differentiation

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.

scholarly journals Adoptive Cell Therapy of Induced Regulatory T Cells Expanded by Tolerogenic Dendritic Cells on Murine Autoimmune Arthritis

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Jie Yang ◽  
Lidong Liu ◽  
Yiming Yang ◽  
Ning Kong ◽  
Xueyu Jiang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
Cell Differentiation ◽  
Regulatory T Cells ◽  
Th17 Cell ◽  
T Cell Proliferation ◽  
Autoimmune Arthritis ◽  
Th17 Cell Differentiation ◽  
Tolerogenic Dendritic Cells

Objective.Tolerogenic dendritic cells (tDCs) can expand TGF-β-induced regulatory T cells (iTregs); however, the therapeutic utility of these expanded iTregs in autoimmune diseases remains unknown. We sought to determine the properties of iTregs expanded by mature tolerogenic dendritic cells (iTregmtDC) in vitro and explore their potential to ameliorate collagen-induced arthritis (CIA) in a mouse model.Methods. After induction by TGF-βand expansion by mature tDCs (mtDCs), the phenotype and proliferation of iTregmtDCwere assessed by flow cytometry. The ability of iTregs and iTregmtDCto inhibit CD4+T cell proliferation and suppress Th17 cell differentiation was compared. Following adoptive transfer of iTregs and iTregmtDCto mice with CIA, the clinical and histopathologic scores, serum levels of IFN-γ, TNF-α, IL-17, IL-6, IL-10, TGF-βand anti-CII antibodies, and the distribution of the CD4+Th subset were assessed.Results. Compared with iTregs, iTregmtDCexpressed higher levels of Foxp3 and suppressed CD4+T cell proliferation and Th17 cell differentiation to a greater extent. In vivo, iTregmtDCreduced the severity and progression of CIA more significantly than iTregs, which was associated with a modulated inflammatory cytokine profile, reduced anti-CII IgG levels, and polarized Treg/Th17 balance.Conclusion.This study highlights the potential therapeutic utility of iTregmtDCin autoimmune arthritis and should facilitate the future design of iTreg immunotherapeutic strategies.

scholarly journals Chloroquine reduces Th17 cell differentiation by stimulating T-bet expression in T cells

2020 ◽  
Author(s):  
Rodolfo Thome ◽  
Alexandra Boehm ◽  
Larissa Lumi Watanabe Ishikawa ◽  
Giacomo Casella ◽  
Jaqueline Munhoz ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cell Differentiation

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.

G-CSF-treated donor CD4+ T cells attenuate acute GVHD through a reduction in Th17 cell differentiation

Cytokine ◽  
2012 ◽  
Vol 60 (1) ◽  
pp. 277-283 ◽  
Author(s):  
Young-Don Joo ◽  
Won-Sik Lee ◽  
Hae-Jeong Won ◽  
Soung-Min Lee ◽  
Hye Ran Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Acute Gvhd ◽  
Th17 Cell Differentiation

scholarly journals Neonatal T Helper 17 Responses Are Skewed Towards an Immunoregulatory Interleukin-22 Phenotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Hamid R. Razzaghian ◽  
Zohreh Sharafian ◽  
Ashish A. Sharma ◽  
Guilaine K. Boyce ◽  
Kelsey Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Gene Networks ◽  
Interleukin 22 ◽  
Cell Responses ◽  
Mucocutaneous Candidiasis ◽  
Th17 Cell Differentiation ◽  
A Genome

Newborns are frequently affected by mucocutaneous candidiasis. Th17 cells essentially limit mucosal invasion by commensal Candida spp. Here, we sought to understand the molecular basis for the developmental lack of Th17 cell responses in circulating blood neonatal T cells. Naive cord blood CD4 T cells stimulated in Th17-differentiating conditions inherently produced high levels of the interleukin-22 immunoregulatory cytokine, particularly in the presence of neonatal antigen-presenting cells. A genome-wide transcriptome analysis comparing neonatal and adult naïve CD4 T cells ex vivo revealed major developmental differences in gene networks regulating Small Drosophila Mothers Against Decapentaplegic (SMAD) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. These changes were functionally validated by experiments showing that the requirement for TGF-β in human Th17 cell differentiation is age-dependent. Moreover, STAT3 activity was profoundly diminished while overexpression of the STAT3 gene restored Th17 cell differentiation capacity in neonatal T cells. These data reveal that Th17 cell responses are developmentally regulated at the gene expression level in human neonates. These developmental changes may protect newborns against pathological Th17 cell responses, at the same time increasing their susceptibility to mucocutaneous candidiasis.

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