Liver X receptors are required for thymic resilience and T cell output

Abstract

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)—a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity—critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ’s functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ’s indispensable roles in adaptive immunity.

The versatility of liver X receptors in T cell homeostasis: Location, location, location!

“…Complementarily, the study by Michaels et al (2020) demonstrates that LXRβ not only regulates thymocyte development, but also effector functions of mature T cells. Specifically, they investigated T cell phenotypes using a CD4-Cre LXRβ knockout mouse model and observed, similar to the study by Chan et al (2020), T cell lymphopenia, decreased proliferative capacity, and also spontaneous T cell activation. Using elegant experiments with bone marrow chimeric mice harboring mixed wild-type and LXRdeficient T cells, the authors found that LXRβ is cell-intrinsically required for T cell fitness and effector T cell (T EFF ) development, and that spontaneous T cell activation may derive from deficient regulatory T (T reg) cell functions.…”

“…Together, the present studies indicate that cell type-specific differential LXR expression and function are likely directly linked to cell type-distinct responses toward LXR deletion or ligand-induced increased activity. These observations, as described by Chan et al (2020) and together with the fact that different NRs are able to cooperate, point out that LXR-mediated actions have to be carefully interpreted when effects cannot be related to specific cellular events. This represents another crucial Cell type-distinct functions of LXRs (LXRα/β) in the regulation of T cell development and function in the thymus and periphery.…”

“…The studies presented by Chan et al (2020) and Michaels et al (2020) provided detailed mechanistic and metabolic evidence for why LXR in T cells could be an interesting pharmacological target. Cell type-specific and context-dependent abrogation of LXRαβ, LXRβ, or even a single copy loss illustrated diverse LXR activities across several cell lineages, resulting in different and independent phenotypes.…”

“…In this issue of JEM, both presented studies address this question using comprehensive genetic models. Chan et al (2020) demonstrate in their study the cell type-specific role and relevance of LXRαβ for T cell development in different cell lineages within the thymus. While LXRαβ-deficient macrophages were shown to accumulate lipids, thymic epithelial cell (TEC)-specific deletion resulted in increased sensitivity to thymic involution due to reduced proliferation capacity, resulting in insufficient TEC self-renewal and recovery.…”

Liver X receptors regulate natural killer T cell population and antitumor activity in the liver of mice

“…A recent report by Chan et al . shows that LXRα and LXRβ are involved in thymic T cell development through mechanisms of action on multiple cell types, including TECs and thymocytes 47 . Developmental stages of iNKT cells are partly overlapped with those of conventional T cells but are distinct such as in NK1.1 expression 3 .…”