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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2012-01-01
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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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