1,721,034 research outputs found
Recommended from our members
Regulators of a regulator: microRNAs in control of regulatory T cell biology
Full text linkMicroRNAs (miRNAs), a class of small non-coding RNA molecules, are key nodes in regulatory networks that fine-tune gene expression and orchestrate diverse signaling pathways that shape immune responses. Since the first study of Dicer-dependent miRNA pathway in regulatory T (Treg) cells in more than a decade ago, miRNAs have been shown to serve as key regulatory elements in controlling the development and function of this specialized CD4+ T cell subset that is indispensable for maintaining immune tolerance and homeostasis. Nevertheless, despite the rapidly accumulating knowledge of the role of miRNAs in Treg cells, our understanding of the intricate regulations of miRNAs and their targets in regulating different aspects of Treg cell biology remains limited. In this work, we demonstrate a critical role for miR-155, which ensures proper Treg cell development in the thymus. Specifically, in addition to the previously reported function of miR-155 in conferring Treg cell competitive fitness, we uncover a novel miR-155-TGFβ axis in the thymic medulla that determines medullary thymic epithelial cell (mTEC) maturity and, consequently, the quantity of thymic Treg cells. In addition to miR-155, we also identify another miRNA family, miR-15/16 that plays an important role in restricting Treg cell function and homeostasis. To this end, we find that the miR-15/16 family, miR-15b/16-2 in particular, is specifically up-regulated in Treg cells in the thymus. Nevertheless, this miRNA family does not seem to play a significant role in regulating thymic Treg cell development. Rather, it is important to control effector Treg (eTreg) cell differentiation and function in the periphery. Mechanistically, the miR-15/16 family targets a network of genes, including a transcription factor, IRF4 that are critical for the establishment of the eTreg cell program.
Collectively, our findings highlight both cell-extrinsic and –intrinsic roles of miRNAs mediated by miR-155 and miR-15/16, respectively in controlling Treg cell biology. Our work not only reveals novel mechanisms by which miRNAs regulate Treg cell-mediated immune tolerance but also provides molecular insights that will undoubtedly aid in developing innovative strategies targeting Treg cells to treat a wide range of immunological disorders
Recommended from our members
The Role of the MicroRNA-23-27-24 Family in Intratumoral Regulatory T-cells
No full textMicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the transcriptome by degrading or suppressing the translation of target mRNAs. Loss of the microRNA network in regulatory T-cells (Tregs) leads to the development of systemic autoimmunity and inflammation due to loss of immunological control. Previously our lab discovered critical roles of the miR-23-27-24 (miR-23) family in controlling the differentiation and function of follicular helper and effector T-cells. To explore the functions of the entire miR-23 family in Tregs, we utilized a transplantable tumor model. We found that loss of the miR-23 family in Tregs impeded tumor growth and reduced Treg frequency. However, there was no apparent increase in the effector functions of antitumor CD8+ T-cells because miR-23 deficient Tregs were more suppressive, compensating for reduced intratumoral Tregs. This increase in suppression is potentially attributed to an increase in IL-10, a target of miR-27. Further profiling of the immune cell landscape found an increase in Natural Killer (NK) cells, which have been shown to be activated by IL-10. The transcription factor TCF1, a target of miR-24, was found to be increased in miR-23 family deficient intratumoral Tregs, leading to a loss of TCF1- effector Tregs. RNA-sequencing found that loss of the miR-23 family in intratumoral Tregs led to a reduction in IL2-STAT5 signaling. Collectively, our work demonstrates that loss of the miR-23 family in Tregs leads to enhanced suppression, potentially due to increased IL-10, loss of TCF1- Tregs, and impaired proliferative capacity
Recommended from our members
Cell Intrinsic Role of MicroRNA-23-27-24 Family in Germinal Center B Cells
Full text linkElevated expression of microRNA-23~27~24 (miR-23) family in T cells has been shown to be crucial to restrict follicular helper T (TFH) cell response. Interestingly, like Bcl-6 and many other molecules that play important roles in both TFH cells and germinal center (GC) B cells, two key components in orchestrating proper humoral immunity, we have found that the miR-23 family is also upregulated in germinal center (GC) B cells. Nevertheless, the cell intrinsic role of this miRNA family in regulating GC B cell response has yet to be characterized. In this study, through employing cell type specific gain-of-function and lost-of function approaches, we show the miR-23 family plays an equally important role in regulating GC B cell responses. However, while the entire miR-23 clusters coordinately limit GC B cell responses, individual members of the miR-23 family contribute to GC B cell regulation in distinct manners. Moreover, despite the fact that GC B cell responses were clearly impacted by the deletion or overexpression of the miR-23 family in B cells, the frequencies of TFH cells in those mice remained unchanged. These results implied that while the miR-23 family serves as negative regulators in limiting GC B cell differentiation and function, they might also play a positive role in promoting GC B/TFH cell interaction. Consistent with this notion, our RNA-seq analysis revealed a network of genes involved in GC B cell biology that are respectively up- and down-regulated in the absence of miR-23 family-mediated regulation. Collectively, our work demonstrates that the miR-23 clusters are pivotal molecular regulators to ensure proper GC B cell responses not only through targeting TFH cells as shown previously but also by directly inhibiting GC B cells in a cell-intrinsic manner
Recommended from our members
A Non-redundant Role for Thymic Epithelial MicroRNA-155 in the Generation of Tregs
Full text linkmiR-155 is a non-coding RNA that is highly upregulated in regulatory T-cells (Tregs), the adaptive immune cells specialized in suppressing autoreactive T cells in order to maintain tolerance and homeostasis. While several studies have confirmed the importance of miR-155 in modulating IL-2R sensitivity to maintain Treg homeostasis, alternative pathways through which miR-155 regulates Treg development remain to be elucidated. In addition to its role in T cells, through taking cell-type specific gene targeting approaches, we demonstrate that miR-155 in Thymic Epithelial Cells (TECs) is equally important in promoting thymic Treg (tTreg) development. In particular, we show that CD80hiMHC IIhi medullary TECs (mTECs), a mature mTEC subset crucial for the generation of tTregs, express high levels of miR-155 and that deletion of TEC-specific miR-155 led to a selective reduction in this mTEC population. Further investigation into the role of thymic epithelial miR-155 pointed to a potential mechanism whereby miR-155 targeting of SMAD3 attenuates TGF-β signaling in mTECs. As the role of TGF-β signaling in controlling the generation of mTECs has been previously established, here we propose a miR-155-SMAD3 axis that regulates TGF-β signaling in the thymic medulla to determine mTEC maturity and, in consequence, the quantity of developing tTregs
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Recommended from our members
The Role of Nod-like Receptor Protein 3 in Gut-Resident Regulatory T Cells
Full text linkRegulatory T (Treg) cells are a subset of adaptive immune cells known for their immunosuppressive functions. Emerging evidence demonstrates that Treg exist throughout the body in tissue-specific sub-populations with specialized functions. RNA-seq analysis performed on mice during systemic autoimmune inflammation revealed high expression levels of Nod-like receptor protein 3 (NLRP3) in gut-resident Treg cells. NLRP3 is part of well-characterized inflammasome commonly associated with innate immune cells, but is beginning to be appreciated in adaptive immune cells as well. To determine the role of NLRP3 in gut-resident Treg-mediated immunosuppression, we generated bone marrow chimeras (BMC) and found that NLRP3-deficiency in Treg cells does not contribute to Treg development or homeostasis, but does result in increased Teff production of IL-17A in the colon. Moreover, in an adoptive T cell transfer model of colitis, co-transfer of NLRP3KO Treg cells failed to rescue Rag-/- recipient mice from weight loss and led to increased Teff production of IFN- and IL-17A in the colon. Moreover, to gain further insights into the role of NLRP3 in Treg cells, in addition to the aforementioned studies with NLRP3KO Treg cells, we also generated a mouse model in which NLRP3 is constitutively-activated in a Treg-specific manner (Foxp3creNLRP3iCA). After immunologically challenging these mice via Citrobacter rodentium, we have shown that colonic Foxp3creNLRP3iCATreg cells exhibit enhanced control over Teff production of IFN- which could potentially impact bacterial clearance. Collectively, by taking both loss-of-function and gain-of-function approaches, our data reveals a pivotal role of NLRP3 in gut-associated Treg cells in maintaining intestinal homeostasis
Recommended from our members
The spontaneous neoantigen-specific CD4+ T cell response to a growing tumor is functionally and phenotypically diverse
No full textAlthough the efficacy of many successful immunotherapies is leveraged by T cells specific for neoantigens (NeoAg), non-self-derived antigens expressed by tumors which typically arise from point mutations, the progressive growth of tumors expressing immunogenic mutations suggests that an effective endogenous immune response is avoided or suppressed. CD4+ T cells play critical roles in the regulation of cellular immunity through the myriad subsets they can comprise but little is known about their development in response to progressive tumor growth, which limits the ability to evaluate therapeutic opportunities and efficacies. I characterized the endogenous NeoAg-specific CD4+ T cell response to a validated clathrin NeoAg (CLTCH129>Q) expressed by SCC VII, an aggressively and poorly immunogenic MHC-II-deficient tumor, using flow cytometry and a CLTCH129>Q/I-Ak tetramer throughout progressive tumor growth. We find that the natural CD4+ T cell response to a growing tumor is phenotypically and functionally diverse, with distinct subsets including type 1 helper (Th1), T follicular helper (Tfh)-like, and regulatory T cell (Treg) lineages appearing as early as 9 days after tumor inoculation. Therapeutic vaccination substantially alters the relative ratio of these subsets by sharply reducing Treg frequency among CLTCH129>Q-specific CD4+ T cells in both the tumor and tumor-draining lymph node (tdLN). Single cell transcriptomic analysis of CLTCH129>Q/I-Ak tetramer-binding CD4+ T cells recapitulated and extended the diversity of the response while permitting profiling of discovered TCRs following transduction into CD4+ T cells. TCRs of varying affinity are found within each functional subset and while affinity played no role in phenotypic fate, adoptive cellular therapies (ACT) using Th1 cells transduced with a Treg-associated TCR were still capable of mediating therapy equally well as those found on cells expressing anti-tumor phenotypes. These findings offer an unprecedented insight into the functional diversity of a natural neoantigen-specific CD4+ T cell response and show how immunotherapeutic intervention influences the phenotype, magnitude, and efficacy of the anti-tumor immune response
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
- …
