Identification of LKLF-regulated genes in quiescent CD4 T lymphocytes

Haaland, Richard E.; Yu, Wendong; Rice, Andrew P.

doi:10.1016/j.molimm.2004.09.012

Cited by 54 publications

(57 citation statements)

References 35 publications

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“…Recent studies have identified the transcription factor FOXO1 as a master regulator of CD62-L transcription, likely via the expression of KLF2. In quiescent T cells, active FOXO1 in the nucleus maintains expression of KLF2, which regulates the expression of CCR7 and CD62-L (15)(16)(17)(21)(22)(23)(24)(25)(26). However, mycolactone reduced the transcription of CD62-L without modulating the expression of KLF2 (Fig.…”

Section: Discussionmentioning

confidence: 96%

Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

Guenin-Macé

Carrette

Asperti-Boursin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mycolactone is a macrolide produced by Mycobacterium ulcerans with immunomodulatory properties. Here, we describe that in mouse, mycolactone injection led to a massive T-cell depletion in peripheral lymph nodes (PLNs) that was associated with defective expression of L-selectin (CD62-L). Importantly, preexposure to mycolactone impaired the capacity of T cells to reach PLNs after adoptive transfer, respond to chemotactic signals, and expand upon antigenic stimulation in vivo. We found that mycolactone-induced suppression of CD62-L expression by human primary T cells was induced rapidly at both the mRNA and protein levels and correlated with the reduced expression of one miRNA: let-7b. Notably, silencing of let-7b was sufficient to inhibit CD62-L gene expression. Conversely, its overexpression tended to up-regulate CD62-L and counteract the effects of mycolactone. Our results identify T-cell homing as a biological process targeted by mycolactone. Moreover, they reveal a mechanism of control of CD62-L expression involving the miRNA let-7b.

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Section: Discussionmentioning

confidence: 96%

Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

Guenin-Macé

Carrette

Asperti-Boursin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Rather, these are genes that are not specifically affected by T-cell costimulation. This was a bit unexpected since quiescent cells actively maintain their phenotype by the expression of LKLF-regulated genes (24,30). None of these genes were targets for integration in this system.…”

Section: The Study Of Hiv Infection In Quiescent Cd4mentioning

confidence: 96%

“…The lack of viral protein expression in latently infected quiescent T cells suggests that the integration sites may be distinct in this cell subset. T-cell quiescence is not a default but rather an actively maintained state regulated by lung Krüppel-like factor (LKLF) and Tob (24,30). Thus, patterns of cellular gene expression in quiescent CD4…”

Section: Quiescent Cd4mentioning

confidence: 99%

“…The similarities found in the integration patterns between stimulated and quiescent CD4 ϩ T cells prompted us to examine the expression levels of genes that hosted HIV integration sites in both cell types. Quiescent T cells actively maintain their phenotype by the expression of a set of genes regulated by LKLF and Tob (24,30). In addition, transcriptional activity in these cells is lower than that in activated cells, and chromatin is tightly packed (5,28).…”

Section: Vol 83 2009 Hiv Integration In Quiescent T Cells 6225mentioning

confidence: 99%

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Human Immunodeficiency Virus Integration Efficiency and Site Selection in Quiescent CD4 ⁺ T Cells

Vatakis

Kim

et al. 2009

J Virol

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Until very recently, quiescent CD4؉ T cells were thought to be resistant to human immunodeficiency virus (HIV) infection. Subsequent studies, attempting to fully elucidate the mechanisms of resistance, showed that quiescent cells could become infected by HIV at low efficiency and form a latently infected population. In this study, we set out to identify the sites of viral integration and to assess the efficiency of the overall integration process in quiescent cells. Based on our results, HIV integration in quiescent CD4؉ T cells occurs in sites similar to those of their prestimulated counterparts. While site selections are similar, the integration process in quiescent cells is plagued by the formation of high levels of incorrectly processed viral ends and abortive two-long-terminal-repeat circles. Quiescent CD4ϩ T cells have been shown to be resistant to human immunodeficiency virus (HIV) infection, and the resistance is characterized by incomplete reverse transcription (82,83). However, the permissiveness of other nondividing cell types, such as resting T cells and macrophages, raised further questions regarding the nature of the block (10,26,56,65,67,(69)(70)(71). Later studies further elucidated which subsets of resting cells were refractory to infection. Truly quiescent cells in the G 0/1a phase were resistant to infection, while cells in the G 1b phase, characterized by high levels of RNA synthesis but not DNA synthesis, were susceptible to infection (43). These combined studies suggested that certain nondividing cells could support a productive infection. Subsequent studies were aimed at further examining the different steps of the viral life cycle in quiescent cells, as well as identifying potential cellular factors or the lack thereof that may block infection. One potential block to infection was hypothesized to be the lack of raw materials such as nucleotides. Treatment of quiescent cells with nucleosides resulted in increased reverse transcription but did not lead to a productive infection following stimulation of the cells (42, 61), suggesting that other factors may contribute to the resistance to productive infection. Recent studies examined the presence or absence of cellular factors responsible for the block in quiescent CD4 ϩ T cells. Both Murr1 and APOBEC3G have been shown to influence the viral life cycle in quiescent CD4 ϩ T cells (18, 29). However neither factor fully explains the lack of rescue of productive infection if quiescent cells are stimulated subsequent to infection.A more detailed examination of the viral life cycle in quiescent CD4 ϩ T cells can shed more light on the nature of the block presented by quiescent CD4 ϩ T cells. A series of recent studies looking at the different stages of the HIV life cycle in quiescent cells have further supported data from our earlier work (82, 83). More specifically, it has been shown that reverse transcription is inefficient in quiescent cells, generating fulllength viral transcripts that are very labile (half-life of 1 day) but are integration co...

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“…Second, overexpression studies suggest that there is a direct causal relationship in gene expression between KLF2 and S1P1. Haaland et al (36) reported that S1P1 was one of the most highly up-regulated genes upon KLF2 induction in Jurkat T cells. Our retroviral transduction studies show that this regulation also occurs in primary T cells.…”

Section: Klf2 Regulates S1p1 Transcription In T Cellsmentioning

confidence: 99%

Krüppel-Like Factor 2 Controls T Cell Trafficking by Activating L-Selectin (CD62L) and Sphingosine-1-Phosphate Receptor 1 Transcription

Bai

Yeung

et al. 2007

The Journal of Immunology

160

172

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Krüppel-like factor 2 (KLF2) is a member of zinc-finger transcription factors. Based on its expression in naive and memory T cells and the activated phenotype of few T cells in mice lacking KLF2 in the lymphoid lineage, KLF2 is postulated to regulate T cell homeostasis by promoting cell quiescence. In this study, we show that in reporter gene assays KLF2 directly activates the promoters of both CD62L and sphingosine-1-phosphate receptor 1 (S1P1), whose expression is critical for T cell egress from the thymus and homing to the lymph nodes. Correspondingly, exogenous KLF2 expression in primary T cells significantly up-regulates both CD62L and S1P1. Following adoptive transfer, KLF2-transduced T cells are much more efficient in homing to lymphoid organs than nontransduced T cells. These findings suggest that KLF2 regulates T cell homeostasis at least partly by controlling CD62L and S1P1 expression, and therefore T cell egress from the thymus and circulation in the periphery.

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Identification of LKLF-regulated genes in quiescent CD4 T lymphocytes

Cited by 54 publications

References 35 publications

Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

Human Immunodeficiency Virus Integration Efficiency and Site Selection in Quiescent CD4 ⁺ T Cells

Krüppel-Like Factor 2 Controls T Cell Trafficking by Activating L-Selectin (CD62L) and Sphingosine-1-Phosphate Receptor 1 Transcription

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Identification of LKLF-regulated genes in quiescent CD4 T lymphocytes

Cited by 54 publications

References 35 publications

Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression

Human Immunodeficiency Virus Integration Efficiency and Site Selection in Quiescent CD4 + T Cells

Krüppel-Like Factor 2 Controls T Cell Trafficking by Activating L-Selectin (CD62L) and Sphingosine-1-Phosphate Receptor 1 Transcription

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Human Immunodeficiency Virus Integration Efficiency and Site Selection in Quiescent CD4 ⁺ T Cells