Medicine (St Vincent's) - Research Publications

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Author: Chong, Mark × End date: 2009 × Start date: 2003 ×

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    Virus-host interactions: new insights from the small RNA
    Browne, EP ; Li, JJ ; Chong, M ; Littman, DR (BMC, 2005)
    RNA silencing has a known role in the antiviral responses of plants and insects. Recent evidence, including the finding that the Tat protein of human immunodeficiency virus (HIV) can suppress the host's RNA-silencing pathway and may thus counteract host antiviral RNAs, suggests that RNA-silencing pathways could also have key roles in mammalian virus-host interactions.
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    Runx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells
    Rudra, D ; Egawa, T ; Chong, MMW ; Treuting, P ; Littman, DR ; Rudensky, AY (NATURE PUBLISHING GROUP, 2009-11)
    The transcription factor Foxp3 has an indispensable role in establishing stable transcriptional and functional programs of regulatory T cells (T(reg) cells). Loss of Foxp3 expression in mature T(reg) cells results in a failure of suppressor function, yet the molecular mechanisms that ensure steady, heritable Foxp3 expression in the T(reg) cell lineage remain unknown. Using T(reg) cell-specific gene targeting, we found that complexes of the transcription factors Runx and CBFbeta were required for maintenance of Foxp3 mRNA and protein expression in T(reg) cells. Consequently, mice lacking CBFbetab exclusively in the T(reg) cell lineage had a moderate lymphoproliferative syndrome. Thus, Runx-CBFbeta complexes maintain stable high expression of Foxp3 and serve as an essential determinant of T(reg) cell lineage stability.
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    Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells
    Klunker, S ; Chong, MMW ; Mantel, P-Y ; Palomares, O ; Bassin, C ; Ziegler, M ; Rueckert, B ; Meiler, F ; Akdis, M ; Littman, DR ; Akdis, CA (ROCKEFELLER UNIV PRESS, 2009-11-23)
    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-beta (TGF-beta) 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-beta (CBFbeta) 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 Cbfb(F/F) CD4-cre naive T cells into Rag2(-/-) mice. Both RUNX1 and RUNX3 siRNA silenced human T reg cells and Cbfb(F/F) CD4-cre mouse T reg cells showed diminished suppressive function in vitro. Circulating human CD4(+) CD25(high) CD127(-) T reg cells significantly expressed higher levels of RUNX3, FOXP3, and TGF-beta 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-beta-induced Foxp3 expression in iT reg cell differentiation and function.
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    The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease (vol 205, pg 2005, 2008)
    Chong, MMW ; Rasmussen, JP ; Rudensky, AY ; Littman, DR (ROCKEFELLER UNIV PRESS, 2008-09-29)
    MicroRNAs (miRNAs) are implicated in the differentiation and function of many cell types. We provide genetic and in vivo evidence that the two RNaseIII enzymes, Drosha and Dicer, do indeed function in the same pathway. These have previously been shown to mediate the stepwise maturation of miRNAs (Lee, Y., C. Ahn, J. Han, H. Choi, J. Kim, J. Yim, J. Lee, P. Provost, O. Radmark, S. Kim, and V.N. Kim. 2003. Nature. 425:415-419), and genetic ablation of either within the T cell compartment, or specifically within Foxp3(+) regulatory T (T reg) cells, results in identical phenotypes. We found that miRNA biogenesis is indispensable for the function of T reg cells. Specific deletion of either Drosha or Dicer phenocopies mice lacking a functional Foxp3 gene or Foxp3(+) cells, whereas deletion throughout the T cell compartment also results in spontaneous inflammatory disease, but later in life. Thus, miRNA-dependent regulation is critical for preventing spontaneous inflammation and autoimmunity.
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    Suppressor of cytokine signaling-1 is a critical regulator of interleukin-7-dependent CD8+ T cell differentiation
    Chong, MMW ; Cornish, AL ; Darwiche, R ; Stanley, EG ; Purton, JF ; Godfrey, DI ; Hilton, DJ ; Starr, R ; Alexander, WS ; Kay, TWH (CELL PRESS, 2003-04)
    To determine the tissue-specific functions of SOCS-1, mice were generated in which the SOCS-1 gene could be deleted in individual tissues. A reporter gene of SOCS-1 promoter activity was also inserted. Using the reporter, high SOCS-1 expression was found at the CD4(+)CD8(+) stage in thymocyte development. To investigate the function of this expression, the SOCS-1 gene was specifically deleted throughout the thymocyte/T/NKT cell compartment. Unlike SOCS-1(-/-) mice, these mice did not develop lethal multiorgan inflammation but developed multiple lymphoid abnormalities, including enhanced differentiation of thymocytes toward CD8(+) T cells and very high percentages of peripheral CD8(+) T cells with a memory phenotype (CD44(hi)CD25(lo)CD69(lo)). These phenotypes were found to correlate with hypersensitivity to the gamma-common family of cytokines.