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Inhibitory Effects of Apoptotic Microparticles on Dendritic Cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Inhibitory Effects of Apoptotic Microparticles on Dendritic Cells./
Author:	Ensanyat, Shaheen.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	48 p.
Notes:	Source: Masters Abstracts International, Volume: 82-12.
Contained By:	Masters Abstracts International82-12.
Subject:	Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28542800
ISBN:	9798515255923

Inhibitory Effects of Apoptotic Microparticles on Dendritic Cells.
Ensanyat, Shaheen.

Inhibitory Effects of Apoptotic Microparticles on Dendritic Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 48 p.

Source: Masters Abstracts International, Volume: 82-12.

Thesis (M.S.)--Icahn School of Medicine at Mount Sinai, 2021.

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

Acute HIV-1 infection results in dysregulated immunity, which contributes to poor control of viral infection. Dendritic cells (DCs) are key regulators of both innate and adaptive immune responses needed for controlling HIV-1. Our lab has previously shown that plasma from patients with acute HIV specifically inhibited DC function, as demonstrated by a decrease in proinflammatory cytokine production (IL-12p70, IL-6, and TNF-a), as well as reduced Th1 priming and NK cell activation. This inhibition was mediated by elevated apoptotic microparticles (Apo MPs) derived from dying cells during acute HIV-1 infection rather than the virus itself. DCs pretreated with Apo MPs derived from peripheral blood monocytes displayed the same inhibitory phenotype when stimulated with the TLR3 agonist, Poly(I:C), compared to DCs pretreated with Ctrl MPs from non-UV irradiated PBMCs. The hyaluronate receptor CD44 may bind Apo MPs and in part mediate this suppressive effect in monocyte-derived DCs (Mo-DCs).Recent studies in our lab have further shown that this Apo MP inhibition may also be due to less Poly(I:C) endocytosis by DCs. Unlike Ctrl MPs, Apo MPs often coat the surface of DCs and may sterically hinder the entry of endosomal TLR agonists, as evidenced by confocal microscopy. Similarly, DCs show reduced maturation (CD80, CD83, CD86) by Poly(I:C) when pretreated with Apo MPs. This DC inhibition may thus partly result from less TLR activation rather than a specific inhibitory pathway. Indeed, there is no significantly enriched suppressive signal by RNA-Seq and Gene Set Enrichment Analysis (GSEA) for DCs pretreated with Apo MPs and stimulated with Poly(I:C). Interestingly, colocalization and flow staining studies further reveal that Apo MPs interact more with RNA and DNA TLR agonists (Poly(I:C), CpG A/B) compared to Ctrl MPs. Therefore, Apo MPs may inhibit DC function by sequestering charged TLR agonists, preventing their endocytosis.Future studies will focus on further characterizing the nature of this inhibitory effect by searching for potential Apo MP receptors on DCs as well as elucidating the interaction between Apo MPs and RNA and DNA TLR agonists. Moreover, we will determine whether this Apo MPs inhibition occurs in different DC subsets (CD141, CD1c, pDC) and is TLR-specific or seen in other maturation stimuli. We will further investigate the kinetics and potency of this DC suppression with time point and titration experiments. RNA-Seq analysis will also be performed to assess the endogenous transcriptomic effects of Apo MP interaction with DCs outside of TLR stimulation. Lastly, we will explore ways to improve DC processing of Apo MPs by manipulating their membrane properties, such as Fc conjugation, chelation, and protease digestion, that hopefully will lead to a robust reversal of inhibition.

ISBN: 9798515255923Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Inhibitory effects

Inhibitory Effects of Apoptotic Microparticles on Dendritic Cells.
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300 $a 48 p.
500 $a Source: Masters Abstracts International, Volume: 82-12.
500 $a Includes supplementary digital materials.
500 $a Advisor: Bhardwaj, Nina.
502 $a Thesis (M.S.)--Icahn School of Medicine at Mount Sinai, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Acute HIV-1 infection results in dysregulated immunity, which contributes to poor control of viral infection. Dendritic cells (DCs) are key regulators of both innate and adaptive immune responses needed for controlling HIV-1. Our lab has previously shown that plasma from patients with acute HIV specifically inhibited DC function, as demonstrated by a decrease in proinflammatory cytokine production (IL-12p70, IL-6, and TNF-a), as well as reduced Th1 priming and NK cell activation. This inhibition was mediated by elevated apoptotic microparticles (Apo MPs) derived from dying cells during acute HIV-1 infection rather than the virus itself. DCs pretreated with Apo MPs derived from peripheral blood monocytes displayed the same inhibitory phenotype when stimulated with the TLR3 agonist, Poly(I:C), compared to DCs pretreated with Ctrl MPs from non-UV irradiated PBMCs. The hyaluronate receptor CD44 may bind Apo MPs and in part mediate this suppressive effect in monocyte-derived DCs (Mo-DCs).Recent studies in our lab have further shown that this Apo MP inhibition may also be due to less Poly(I:C) endocytosis by DCs. Unlike Ctrl MPs, Apo MPs often coat the surface of DCs and may sterically hinder the entry of endosomal TLR agonists, as evidenced by confocal microscopy. Similarly, DCs show reduced maturation (CD80, CD83, CD86) by Poly(I:C) when pretreated with Apo MPs. This DC inhibition may thus partly result from less TLR activation rather than a specific inhibitory pathway. Indeed, there is no significantly enriched suppressive signal by RNA-Seq and Gene Set Enrichment Analysis (GSEA) for DCs pretreated with Apo MPs and stimulated with Poly(I:C). Interestingly, colocalization and flow staining studies further reveal that Apo MPs interact more with RNA and DNA TLR agonists (Poly(I:C), CpG A/B) compared to Ctrl MPs. Therefore, Apo MPs may inhibit DC function by sequestering charged TLR agonists, preventing their endocytosis.Future studies will focus on further characterizing the nature of this inhibitory effect by searching for potential Apo MP receptors on DCs as well as elucidating the interaction between Apo MPs and RNA and DNA TLR agonists. Moreover, we will determine whether this Apo MPs inhibition occurs in different DC subsets (CD141, CD1c, pDC) and is TLR-specific or seen in other maturation stimuli. We will further investigate the kinetics and potency of this DC suppression with time point and titration experiments. RNA-Seq analysis will also be performed to assess the endogenous transcriptomic effects of Apo MP interaction with DCs outside of TLR stimulation. Lastly, we will explore ways to improve DC processing of Apo MPs by manipulating their membrane properties, such as Fc conjugation, chelation, and protease digestion, that hopefully will lead to a robust reversal of inhibition.
590 $a School code: 1734.
650 4 $a Immunology. $3 611031
650 4 $a Biomedical engineering. $3 535387
650 4 $a Genetics. $3 530508
650 4 $a Virology. $3 642304
653 $a Inhibitory effects
653 $a Apoptotic microparticles
653 $a Dendritic cells
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710 2 $a Icahn School of Medicine at Mount Sinai. $b Biomedical Sciences. $3 3191442
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