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LXR signaling couples sterol metabolism to proliferation in the acquired immune response.

ABSTRACT: Cholesterol is essential for membrane synthesis; however, the mechanisms that link cellular lipid metabolism to proliferation are incompletely understood. We demonstrate here that cellular cholesterol levels in dividing T cells are maintained in part through reciprocal regulation of the LXR and SREBP transcriptional programs. T cell activation triggers induction of the oxysterol-metabolizing enzyme SULT2B1, consequent suppression of the LXR pathway for cholesterol transport, and promotion of the SREBP pathway for cholesterol synthesis. Ligation of LXR during T cell activation inhibits mitogen-driven expansion, whereas loss of LXRbeta confers a proliferative advantage. Inactivation of the sterol transporter ABCG1 uncouples LXR signaling from proliferation, directly linking sterol homeostasis to the antiproliferative action of LXR. Mice lacking LXRbeta exhibit lymphoid hyperplasia and enhanced responses to antigenic challenge, indicating that proper regulation of LXR-dependent sterol metabolism is important for immune responses. These results implicate LXR signaling in a metabolic checkpoint that modulates cell proliferation and immunity.

SUBMITTER: Bensinger SJ

PROVIDER: S-EPMC2626438 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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LXR signaling couples sterol metabolism to proliferation in the acquired immune response.

Bensinger Steven J SJ Bradley Michelle N MN Joseph Sean B SB Zelcer Noam N Janssen Edith M EM Hausner Mary Ann MA Shih Roger R Parks John S JS Edwards Peter A PA Jamieson Beth D BD Tontonoz Peter P

Cell 20080701 1

Cholesterol is essential for membrane synthesis; however, the mechanisms that link cellular lipid metabolism to proliferation are incompletely understood. We demonstrate here that cellular cholesterol levels in dividing T cells are maintained in part through reciprocal regulation of the LXR and SREBP transcriptional programs. T cell activation triggers induction of the oxysterol-metabolizing enzyme SULT2B1, consequent suppression of the LXR pathway for cholesterol transport, and promotion of the ...[more]

PMID: 18614014

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Project description:BackgroundIn HIV discordant couples (one parther is HIV-infected, another is HIV-uninfected) HIV-negative partners often remain uninfected for a long time despite long, stable, often unprotected sexual contacts with HIV-infected partner. The increase of time of living together accompanying the decrease of the incidence of HIV infection in HIV-negative partner. The features of HIV-specific immune response in HIV discorgant couples was investigated.MethodsThirty-three HIV discordant couples from Moscow region living together <1 year (2 couples), 1 to 3 years (18 couples), 4 to 5 years (9 couples), 6 to 10 years (4 couples) were included in the investigation. Sera of 33 HIV-uninfected partners from HIV discordant couples (17 men and 16 women) were tested for HIV-specific antibodies by enzyme immunoassay and immunoblot. Viral load was estimated by polymerase chain reaction (PCR).ResultsAntibodies against HIV gp160 were detected in 3 persons (9,1%), against p68/66—in 3 persons (9,1%), against p52/51—in 3 persons (9,1%), against g34/31—in 3 persons (9,1%); total—in 6 persons (18,2%). All of them were defined as HIV-uninfected by PCR. In 4 of 6 persons HIV-specific antibodies were not detected after finishing of risk behavior.ConclusionsIt is possible to suggest that detected antibodies against HIV gp160, p68/66, p52/51, p34/31 in HIV-uninfected people are caused by contact with HIV (according to literature data, non-specific stimulation may cause the appearance of antibodies binding the other HIV antigens: p55, p24/25 and g18) and may contribute to maintainance of HIV-negative status of uninfected partners in HIV-discordant couples. The cohort of high exposed but HIV-uninfected people was formed during immunological monitoring of HIV discordant couples in Moscow region. This cohort is available for systematic observation and is perspective for further investigation of mechanisms of resistance to HIV infection and correlates of immune protection. Now the cohort is expanded.

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LXR signaling couples sterol metabolism to proliferation in the acquired immune response.

Publications

LXR signaling couples sterol metabolism to proliferation in the acquired immune response.

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