TY - JOUR
T1 - Liver X receptors are required for thymic resilience and T cell output
AU - Chan, Christopher T.
AU - Fenn, Ashley M.
AU - Harder, Nina K.
AU - Mindur, John E.
AU - McAlpine, Cameron S.
AU - Patel, Jyoti
AU - Valet, Colin
AU - Rattik, Sara
AU - Iwamoto, Yoshiko
AU - He, Shun
AU - Anzai, Atsushi
AU - Kahles, Florian
AU - Poller, Wolfram C.
AU - Janssen, Henrike
AU - Wong, Lai Ping
AU - Fernandez-Hernando, Carlos
AU - Koolbergen, David R.
AU - van der Laan, Anja M.
AU - Yvan-Charvet, Laurent
AU - Sadreyev, Ruslan I.
AU - Nahrendorf, Matthias
AU - Westerterp, Marit
AU - Tall, Alan R.
AU - Gustafsson, Jan-Ake
AU - Swirski, Filip K.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088848133&partnerID=8YFLogxK
U2 - https://doi.org/10.1084/jem.20200318
DO - https://doi.org/10.1084/jem.20200318
M3 - Article
C2 - 32716519
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
M1 - 20200318
ER -