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Checks and Balances: Transcriptional...

Nazitto, Rodolfo.

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Checks and Balances: Transcriptional Regulation of Myeloid Innate Immunity and Dendritic Cell Maturation.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Checks and Balances: Transcriptional Regulation of Myeloid Innate Immunity and Dendritic Cell Maturation./
Author:	Nazitto, Rodolfo.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	109 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-11, Section: B.
Contained By:	Dissertations Abstracts International82-11B.
Subject:	Cellular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28411641
ISBN:	9798728230878

Checks and Balances: Transcriptional Regulation of Myeloid Innate Immunity and Dendritic Cell Maturation.
Nazitto, Rodolfo.

Checks and Balances: Transcriptional Regulation of Myeloid Innate Immunity and Dendritic Cell Maturation. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 109 p.

Source: Dissertations Abstracts International, Volume: 82-11, Section: B.

Thesis (Ph.D.)--University of Washington, 2021.

This item must not be sold to any third party vendors.

Antigen presenting cells such as myeloid dendritic cells (DCs) are key sentinels of the innate immune system. In response to pathogen recognition and innate immune stimulation, DCs transition from an immature, inactive state to a mature, active state that is characterized by widespread changes in host gene expression, which include the upregulation of cytokines, chemokines, and costimulatory factors to protect against infection. Several transcription factors are known to drive these gene expression changes, but the mechanisms that negatively regulate DC maturation are less well understood. Here, we identify the transcription factor Interleukin Enhancer Binding Factor 3 (ILF3) as a negative regulator of innate immune responses and DC maturation. Depletion of ILF3 in primary human monocyte-derived DCs (MDDCs) led to increased expression of maturation markers and potentiated innate responses during stimulation with viral mimetics or classic innate agonists. Conversely, overexpression of short or long ILF3 isoforms (NF90 and NF110) suppressed DC maturation and innate immune responses. Through mutagenesis experiments, we found that a nuclear localization sequence in ILF3, and not its dual double-stranded RNA-binding domains (dsRBDs), was required for this function. Mutation of the domain associated with zinc finger (DZF) motif of ILF3's NF110 isoform blocked its ability to suppress DC maturation. Moreover, RNA-seq analysis indicated that ILF3 regulates genes associated with cholesterol homeostasis in addition to genes associated with DC maturation. Together, our data establish ILF3 as a transcriptional regulator that restrains DC maturation and limits innate immune responses through a mechanism that may intersect with lipid metabolism.

ISBN: 9798728230878Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Dendritic cell

Checks and Balances: Transcriptional Regulation of Myeloid Innate Immunity and Dendritic Cell Maturation.
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500 $a Advisor: Aderem, Alan.
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506 $a This item must not be sold to any third party vendors.
520 $a Antigen presenting cells such as myeloid dendritic cells (DCs) are key sentinels of the innate immune system. In response to pathogen recognition and innate immune stimulation, DCs transition from an immature, inactive state to a mature, active state that is characterized by widespread changes in host gene expression, which include the upregulation of cytokines, chemokines, and costimulatory factors to protect against infection. Several transcription factors are known to drive these gene expression changes, but the mechanisms that negatively regulate DC maturation are less well understood. Here, we identify the transcription factor Interleukin Enhancer Binding Factor 3 (ILF3) as a negative regulator of innate immune responses and DC maturation. Depletion of ILF3 in primary human monocyte-derived DCs (MDDCs) led to increased expression of maturation markers and potentiated innate responses during stimulation with viral mimetics or classic innate agonists. Conversely, overexpression of short or long ILF3 isoforms (NF90 and NF110) suppressed DC maturation and innate immune responses. Through mutagenesis experiments, we found that a nuclear localization sequence in ILF3, and not its dual double-stranded RNA-binding domains (dsRBDs), was required for this function. Mutation of the domain associated with zinc finger (DZF) motif of ILF3's NF110 isoform blocked its ability to suppress DC maturation. Moreover, RNA-seq analysis indicated that ILF3 regulates genes associated with cholesterol homeostasis in addition to genes associated with DC maturation. Together, our data establish ILF3 as a transcriptional regulator that restrains DC maturation and limits innate immune responses through a mechanism that may intersect with lipid metabolism.
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