scholarly journals A role for Dicer in immune regulation

2006 ◽  
Vol 203 (11) ◽  
pp. 2519-2527 ◽  
Author(s):  
Bradley S. Cobb ◽  
Arnulf Hertweck ◽  
James Smith ◽  
Eric O'Connor ◽  
Daniel Graf ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mirna Profile ◽  
Rnase Iii ◽  
Micro Rnas ◽  
Efficient Induction ◽  
A Cell ◽  
Immune Pathology

Micro RNAs (miRNAs) regulate gene expression at the posttranscriptional level. Here we show that regulatory T (T reg) cells have a miRNA profile distinct from conventional CD4 T cells. A partial T reg cell–like miRNA profile is conferred by the enforced expression of Foxp3 and, surprisingly, by the activation of conventional CD4 T cells. Depleting miRNAs by eliminating Dicer, the RNAse III enzyme that generates functional miRNAs, reduces T reg cell numbers and results in immune pathology. Dicer facilitates, in a cell-autonomous fashion, the development of T reg cells in the thymus and the efficient induction of Foxp3 by transforming growth factor β. These results suggest that T reg cell development involves Dicer-generated RNAs.

scholarly journals Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells

2009 ◽  
Vol 206 (12) ◽  
pp. 2701-2715 ◽  
Author(s):  
Sven Klunker ◽  
Mark M.W. Chong ◽  
Pierre-Yves Mantel ◽  
Oscar Palomares ◽  
Claudio Bassin ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Foxp3 Expression ◽  
Human Tonsil ◽  
Suppressive Function

Forkhead box P3 (FOXP3)+CD4+CD25+ inducible regulatory T (iT reg) cells play an important role in immune tolerance and homeostasis. In this study, we show that the transforming growth factor-β (TGF-β) induces the expression of the Runt-related transcription factors RUNX1 and RUNX3 in CD4+ T cells. This induction seems to be a prerequisite for the binding of RUNX1 and RUNX3 to three putative RUNX binding sites in the FOXP3 promoter. Inactivation of the gene encoding RUNX cofactor core-binding factor-β (CBFβ) in mice and small interfering RNA (siRNA)-mediated suppression of RUNX1 and RUNX3 in human T cells resulted in reduced expression of Foxp3. The in vivo conversion of naive CD4+ T cells into Foxp3+ iT reg cells was significantly decreased in adoptively transferred CbfbF/F CD4-cre naive T cells into Rag2−/− mice. Both RUNX1 and RUNX3 siRNA silenced human T reg cells and CbfbF/F CD4-cre mouse T reg cells showed diminished suppressive function in vitro. Circulating human CD4+ CD25high CD127− T reg cells significantly expressed higher levels of RUNX3, FOXP3, and TGF-β mRNA compared with CD4+CD25− cells. Furthermore, FOXP3 and RUNX3 were colocalized in human tonsil T reg cells. These data demonstrate Runx transcription factors as a molecular link in TGF-β–induced Foxp3 expression in iT reg cell differentiation and function.

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3249-3256 ◽  
Author(s):  
Laurence Weiss ◽  
Vladimira Donkova-Petrini ◽  
Laure Caccavelli ◽  
Michèle Balbo ◽  
Cédric Carbonneil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Subset ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

scholarly journals The interleukin-10 inducing effect of transforming growth factor-β on human naive CD4+ T cells from cord blood is restricted to the TH1 subset

2006 ◽  
Vol 147 (2) ◽  
pp. 352-358
Author(s):  
B. Kapitein ◽  
M. M. Tiemessen ◽  
W. M. Liu ◽  
A. G. Van Ieperen-van Dijk ◽  
M. O. Hoekstra ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Cord Blood ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Molecular profiling of CD3−CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways

Blood ◽  
2009 ◽  
Vol 114 (14) ◽  
pp. 2969-2983 ◽  
Author(s):  
Marie Ravoet ◽  
Catherine Sibille ◽  
Chunyan Gu ◽  
Myriam Libin ◽  
Benjamin Haibe-Kains ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Chronic Disease ◽  
T Cell ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Major Gene ◽  
Hypereosinophilic Syndrome ◽  
Transforming Growth Factor Β ◽  
T Lymphoma

The clonal CD3−CD4+ T-cell population characterizing lymphocytic variant hypereosinophilic syndrome (L-HES) persists for years, with a subgroup of patients ultimately progressing to T lymphoma. The molecular changes associated with the premalignant clone and the emergence of malignant subclones are unknown, precluding the development of targeted therapy for this HES variant. In this study, we used whole genome arrays to examine gene expression in the CD3−CD4+ T cells and found that 850 genes were differentially regulated during chronic disease compared with CD3+CD4+ T cells from healthy donors. Changes in the expression of 349 genes were altered in association with the clinical progression from chronic L-HES to T lymphoma in 1 patient, with 87 of 349 genes representing further changes in genes whose expression was altered in all chronic disease patients (87 of 850). Array analysis after CD2/CD28-mediated activation revealed that the major gene expression changes observed in the CD3−CD4+ T cells do not reflect activation induced alterations but rather pathways involved in T-cell homeostasis, including transforming growth factor-β signaling, apoptosis, and T-cell maturation, signaling, and migration. Examination of microRNA expression in the CD3−CD4+ T cells from patients with chronic disease identified 23 microRNAs that changed significantly, among which miR-125a further decreased in association with one patient's evolution to T lymphoma.

scholarly journals Low-strength T-cell activation promotes Th17 responses

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 4829-4837 ◽  
Author(s):  
Harriet A. Purvis ◽  
Jeroen N. Stoop ◽  
Jelena Mann ◽  
Steven Woods ◽  
Anne E. Kozijn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 17

Abstract We show that the strength of T-cell stimulation determines the capability of human CD4+ T cells to become interleukin-17 (IL-17) producers. CD4+ T cells received either high- (THi) or low (TLo)–strength stimulation via anti-CD3/CD28 beads or dendritic cells pulsed with superantigen in the presence of pro-Th17 cytokines IL-1β, transforming growth factor β, and IL-23. We found that TLo, but not THi, stimulation profoundly promoted Th17 responses by enhancing both the relative proportion and total number of Th17 cells. Titration of anti-CD3 revealed that low TCR signaling promoted Th17 cells, but only in the presence of anti-CD28. Impaired IL-17 production in THi cells could not be explained by high levels of Foxp3 or transforming growth factor β–latency-associated peptide expressed by THi cells. Nuclear factor of activated T cells was translocated to the nucleus in both THi and TLo cells, but only bound to the proximal region of the IL-17 promoter in TLo cells. The addition of a Ca2+ ionophore under TLo conditions reversed the pro-Th17 effect, suggesting that high Ca2+ signaling impairs Th17 development. Although our data do not distinguish between priming of naive T cells versus expansion/differentiation of memory T cells, our results clearly establish an important role for the strength of T-cell activation in regulating Th17 responses.

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