For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
14
views
36
references
 Top references
cited by
76
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      957
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      Activin A programs human T FH cell differentiation

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          SUMMARY

          Follicular helper T (T FH) cells are CD4 + T cells specialized in helping B cells and are associated both with protective antibody responses and autoimmune diseases. The promise of targeting T FH cells therapeutically has been limited by fragmentary understanding of extrinsic signals regulating human T FH cell differentiation. A screen of a human protein library identified activin A as new regulator of T FH cell differentiation. Activin A orchestrated expression of multiple T FH-associated genes, independently or in concert with additional signals. T FH programming by activin A was antagonized by the cytokine IL-2. Activin A’s capacity to drive T FH cell differentiation in vitro was conserved for non-human primates but not mice. Finally, activin A-induced T FH programming was dependent on SMAD2 and SMAD3 signaling and blocked by pharmacological inhibitors.

          Related collections

          Most cited references36

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway

          Stephan Herbertz, J Sawyer, Anja J Stauber … (2015)
          Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.
          Article 0 comments Cited 200 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype.

            Dat Q. Tran, Heather Ramsey, Ethan Shevach (2007)
            Thymic-derived natural T-regulatory cells (nTregs) are important for the induction of self-tolerance and the control of autoimmunity. Murine CD4+CD25(-)Foxp3(-) cells can be induced to express Foxp3 after T-cell receptor (TCR) activation in the presence of transforming growth factor beta (TGFbeta) and are phenotypically similar to nTregs. Some studies have suggested that TCR stimulation of human CD4+CD25(-) cells results in the induction of transient expression of FOXP3, but that the induced cells lack a regulatory phenotype. We demonstrate here that TCR stimulation alone was insufficient to induce FOXP3 expression in the absence of TGFbeta, whereas high levels of FOXP3 expression could be induced in the presence of TGFbeta. Although FOXP3 expression was stable, the TGFbeta-induced FOXP3+ T cells were neither anergic nor suppressive and produced high levels of effector cytokines. These results suggest that even high levels of FOXP3 expression are insufficient to define a human CD4+ T cell as a T-regulatory cell.
            Article 0 comments Cited 166 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              TGF-β co-opts STAT3-STAT4 signaling to promote human T follicular helper cell differentiation

              Nathalie Schmitt, Yang Liu, Salah-Eddine Bentebibel … (2014)
              Understanding the developmental mechanisms of T follicular helper (TFH) cells in humans is a highly relevant topic to clinic. However, factors that drive human CD4+ helper T (TH) cell differentiation program towards TFH cells remain largely undefined. Here we show that TGF-β provides critical additional signals for the transcription factors STAT3 and STAT4 to promote the initial TFH differentiation programs in humans. This mechanism does not appear to be shared with mouse TH cells. The developing human Bcl-6+ TFH cells also expressed RORγt, a transcription factor typically expressed by TH17 cells. Our study documents a mechanism by which TFH and TH17 cells co-emerge in inflammatory environments in humans, as often observed in many human autoimmune diseases.
              Article 0 comments Cited 145 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100941354
                Journal ID (pubmed-jr-id): 21750
                Journal ID (nlm-ta): Nat Immunol
                Journal ID (iso-abbrev): Nat. Immunol.
                Title: Nature immunology
                ISSN (Print): 1529-2908
                ISSN (Electronic): 1529-2916
                Publication date Nihms-submitted: 7 June 2016
                Publication date (Electronic): 04 July 2016
                Publication date (Print): August 2016
                Publication date PMC-release: 04 January 2017
                Volume: 17
                Issue: 8
                Pages: 976-984
                Affiliations
                [1 ]Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, CA 92037, USA
                [2 ]Microscopy Core Facility, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, CA 92037, USA
                [3 ]Genomics Institute of the Novartis Research Foundation (GNF), La Jolla, CA 92121, USA
                [4 ]Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA
                [5 ]Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, CA 92037, USA
                Author notes
                Correspondence should be addressed to S.C. ( shane@ 123456lji.org )
                Article
                Manuscript ID: NIHMS790110
                DOI: 10.1038/ni.3494
                PMC ID: 4955732
                PubMed ID: 27376469
                SO-VID: 7c4a06e2-95ed-4a6d-97c8-20fadbec50f5
                License:

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

                Comments

                Comment on this article

                scite_

                Similar content957

                See all similar

                Cited by76

                See all cited by

                Most referenced authors741

                See all reference authors