Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Publication Date: 2013-06-04
    Description: Through their functional diversification, distinct lineages of CD4(+) T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4(+) T cells. BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within TH1, TH2 and TH17 cell lineages. These findings identify BACH2 as a key regulator of CD4(+) T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710737/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710737/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roychoudhuri, Rahul -- Hirahara, Kiyoshi -- Mousavi, Kambiz -- Clever, David -- Klebanoff, Christopher A -- Bonelli, Michael -- Sciume, Giuseppe -- Zare, Hossein -- Vahedi, Golnaz -- Dema, Barbara -- Yu, Zhiya -- Liu, Hui -- Takahashi, Hayato -- Rao, Mahadev -- Muranski, Pawel -- Crompton, Joseph G -- Punkosdy, George -- Bedognetti, Davide -- Wang, Ena -- Hoffmann, Victoria -- Rivera, Juan -- Marincola, Francesco M -- Nakamura, Atsushi -- Sartorelli, Vittorio -- Kanno, Yuka -- Gattinoni, Luca -- Muto, Akihiko -- Igarashi, Kazuhiko -- O'Shea, John J -- Restifo, Nicholas P -- Z01 BC011037-01/Intramural NIH HHS/ -- Z99 CA999999/Intramural NIH HHS/ -- ZIA BC011037-02/Intramural NIH HHS/ -- England -- Nature. 2013 Jun 27;498(7455):506-10. doi: 10.1038/nature12199. Epub 2013 Jun 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. roychoudhuri@mail.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23728300" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/immunology ; Basic-Leucine Zipper Transcription Factors/deficiency/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/immunology/metabolism ; Cell Differentiation/genetics/immunology ; Female ; Forkhead Transcription Factors/genetics/metabolism ; Homeostasis/genetics/*immunology ; Humans ; Immune Tolerance/genetics/immunology ; Inflammation/genetics/immunology/mortality/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes, Regulatory/cytology/drug effects/*immunology/metabolism ; Transforming Growth Factor beta/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Publication Date: 2018-09-18
    Description: Immune stimulation contributes to lenalidomide’s antitumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood, and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T cell function in vitro. Whether T cell activation is required for clinical response to lenalidomide remains unclear. In this study, we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with antitumor response. Within days of starting lenalidomide, T cells increased in the tumor microenvironment and showed Th1-type polarization. Gene expression profiling of pretreatment and on-treatment lymph node biopsy specimens revealed upregulation of IFN- and many of its target genes in response to lenalidomide. The IFN-–mediated Th1 response was limited to patients achieving a clinical response defined by a reduction in lymphadenopathy. Deep sequencing of TCR genes revealed decreasing diversity of the T cell repertoire and an expansion of select clonotypes in responders. To validate our observations, we stimulated T cells and CLL cells with lenalidomide in culture and detected lenalidomide-dependent increases in T cell proliferation. Taken together, our data demonstrate that lenalidomide induced Th1 immunity in the lymph node that is associated with clinical response.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Publication Date: 2018-08-29
    Description: The cytokines of the transforming growth factor–β (TGF-β) family promote the growth and differentiation of multiple tissues, but the role of only the founding member, TGF-β, in regulating the immune responses has been extensively studied. TGF-β is critical to prevent the spontaneous activation of self-reactive T cells and sustain immune homeostasis. In contrast, in the presence of proinflammatory cytokines, TGF-β promotes the differentiation of effector T helper 17 (T H 17) cells. Abrogating TGF-β receptor signaling prevents the development of interleukin-17 (IL-17)–secreting cells and protects mice from T H 17 cell–mediated autoimmunity. We found that the receptor of another member of TGF-β family, bone morphogenetic protein receptor 1α (BMPR1α), regulates T helper cell activation. We found that the differentiation of T H 17 cells from naive CD4 + T cells was inhibited in the presence of BMPs. Abrogation of BMPR1α signaling during CD4 + T cell activation induced a developmental program that led to the generation of inflammatory effector cells expressing large amounts of IL-17, IFN-, and TNF family cytokines and transcription factors defining the T H 17 cell lineage. We found that TGF-β and BMPs cooperated to establish effector cell functions and the cytokine profile of activated CD4 + T cells. Together, our data provide insight into the immunoregulatory function of BMPs.
    Print ISSN: 1945-0877
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...