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

By S. Bensinger, Michelle N. Bradley, S. Joseph, N. Zelcer, E. Janssen, M. Hausner, R. Shih, J. Parks, P. Edwards, B. Jamieson and 1 more. Cell, 2008

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Summary We demonstrate here that LXR–dependent sterol homeostasis is a physiologically-regulated determinant of cell proliferation and acquired immune responses. T cell activation triggers simultaneous suppression of the LXR pathway for cholesterol transport and induction of the SREBP pathway for cholesterol synthesis. This coordinated program is engaged in part through induction of the sterol-metabolizing enzyme SULT2B1, expression of which in T cells blocks LXR signaling. Forced induction of LXR target genes during T cell activation markedly inhibits mitogen-driven expansion, whereas loss of LXRβ confers a proliferative advantage. Inactivation of the sterol transporter ABCG1 in T cells uncouples LXR signaling from proliferation, directly linking sterol homeostasis to the anti-proliferative action of LXR. Mice lacking LXRβ exhibit lymphoid hyperplasia and enhanced responses to antigenic challenge, indicating that proper regulation of LXR-dependent sterol metabolism is important for immune responses. These data implicate LXR signaling in a metabolic checkpoint that modulates cell proliferation and immunity.

Subfields: Immunology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/85d7b044585a629cea24b7475f17bda186844a04

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Citations in the corpus

HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells (2011, background): “In support of this notion, proper regulation of glucose and sterol metabolism is required for the development of adaptive immune responses (Bensinger and Tontonoz, 2008; Bensinger et al., 2008; Cham et al., 2008).”
Memory CD8+ T cells use cell intrinsic lipolysis to support the metabolic programming necessary for development (2014, background): “in Figures 1A and 1B, indicate that different T cells exhibit distinct preferences for lipid substrates, suggesting that acquisition of lipids that provide cholesterol for membranes and other processes might be different from those that fuel energy metabolism, fitting with published data (Bensinger ”
Metabolic Regulation of T Lymphocytes (2013, background): “In T cells, antigenic stimulation is followed by decreased LXR activity and increased activity of the SREBP-2 pathway for lipid and cholesterol synthesis (51).”
The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. (2015, background): “, 2011b), and the liver X receptors (LXRs) (Bensinger et al., 2008) facilitate T cell metabolic reprogramming by enhancing the expression of metabolic genes downstream of TCR signaling, which allow Teff cells to meet the bioenergetic and biosynthetic requirements of cell division and effector functi”
Nutrient sensing and inflammation in metabolic diseases (2008, background): “For example, activation of nuclear receptors, such as peroxisome-proliferator-activated receptors (PPARs) and liver X receptors (LXRs), can suppress inflammatory pathway”
Apoptotic cells promote their own clearance and immune tolerance through activation of LXR (2009, positive): “Representative images are shown. to increased lymphocyte proliferation (Bensinger et al., 2008).”