Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response.

Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enri...

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Main Authors: Jacqueline Surls, Cristina Nazarov-Stoica, Margaret Kehl, Cara Olsen, Sofia Casares, Teodor-D Brumeanu
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2012-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3378591?pdf=render
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spelling doaj-77aa4cc9ba23459da0260ca447f655352020-11-25T02:20:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0176e3873310.1371/journal.pone.0038733Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response.Jacqueline SurlsCristina Nazarov-StoicaMargaret KehlCara OlsenSofia CasaresTeodor-D BrumeanuCell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40-50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL-2Rα, IL-4Rα, and IL-12Rβ2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen-specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4(+)Foxp3(+) T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response.http://europepmc.org/articles/PMC3378591?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Jacqueline Surls
Cristina Nazarov-Stoica
Margaret Kehl
Cara Olsen
Sofia Casares
Teodor-D Brumeanu
spellingShingle Jacqueline Surls
Cristina Nazarov-Stoica
Margaret Kehl
Cara Olsen
Sofia Casares
Teodor-D Brumeanu
Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response.
PLoS ONE
author_facet Jacqueline Surls
Cristina Nazarov-Stoica
Margaret Kehl
Cara Olsen
Sofia Casares
Teodor-D Brumeanu
author_sort Jacqueline Surls
title Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response.
title_short Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response.
title_full Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response.
title_fullStr Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response.
title_full_unstemmed Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response.
title_sort increased membrane cholesterol in lymphocytes diverts t-cells toward an inflammatory response.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2012-01-01
description Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40-50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL-2Rα, IL-4Rα, and IL-12Rβ2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen-specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4(+)Foxp3(+) T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response.
url http://europepmc.org/articles/PMC3378591?pdf=render
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