Abstract
Cholesterol homeostasis has a pivotal function in regulating immune cells. Here we show that apolipoprotein E (apoE) deficiency leads to the accumulation of cholesterol in the cell membrane of dendritic cells (DC), resulting in enhanced MHC-II-dependent antigen presentation and CD4+ T-cell activation. Results from WT and apoE KO bone marrow chimera suggest that apoE from cells of hematopoietic origin has immunomodulatory functions, regardless of the onset of hypercholesterolemia. Humans expressing apoE4 isoform (ε4/3–ε4/4) have increased circulating levels of activated T cells compared to those expressing WT apoE3 (ε3/3) or apoE2 isoform (ε2/3–ε2/2). This increase is caused by enhanced antigen-presentation by apoE4-expressing DCs, and is reversed when these DCs are incubated with serum containing WT apoE3. In summary, our study identifies myeloid-produced apoE as a key physiological modulator of DC antigen presentation function, paving the way for further explorations of apoE as a tool to improve the management of immune diseases.
Highlights
Cholesterol homeostasis has a pivotal function in regulating immune cells
To investigate the physiological relevance of this phenotype, we analyzed the survival of B6Kd-derived skin grafts transplanted onto WT and apolipoprotein E (apoE) KO mice (Fig. 1f), an alloresponse mediated by both CD8+ and CD4+ T cells[28]
As dendritic cells (DC) of both donor and recipient origin are responsible for the initiation of direct and indirect alloresponses, respectively[39], we investigated whether apoE deficiency impacted DC antigen presentation ability and induction of a primary immune response by T cells
Summary
Cholesterol homeostasis has a pivotal function in regulating immune cells. Here we show that apolipoprotein E (apoE) deficiency leads to the accumulation of cholesterol in the cell membrane of dendritic cells (DC), resulting in enhanced MHC-II-dependent antigen presentation and CD4+ T-cell activation. In the same experimental settings, the overexpression of apolipoprotein A-I (apoA-I), which increases the ability to transport cholesterol back to the liver, results in a reduced cellular cholesterol accumulation and immune cell activation in lymph nodes[18,19] These data point to a critical role for apolipoproteins, including apoA-I and apoE, in controlling cholesterol immunometabolism at both a systemic and cellular level. Our results from experimental models and humans reveal a critical function of myeloid-derived apoE in controlling DC antigen presentation and T-cell priming They further indicate that this apoE function is mediated through the autocrine/paracrine modulation of cholesterol metabolism in DCs, and is independent of systemic hypercholesterolemia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
