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 - Laan, Anja M.Van Der
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.
N1 - Funding Information:
This work was funded by the National Institutes of Health (grants R35 HL135752, P01 HL131478, and P01 HL142494 to F.K.
Funding Information:
Swirski); the American Heart Association Established Investigator Award (grant 17EIA33410439 to F.K. Swirski); and the Patricia and Scott Eston MGH Research Scholar (to F.K. Swirski). C.T. Chan was supported by an American Heart Association Postdoctoral Fellowship (AHA 19POST34380057). N.K. Harder was supported by Boehringer Ingelheim Fonds.
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
UR - http://www.scopus.com/inward/citedby.url?scp=85088848133&partnerID=8YFLogxK
U2 - 10.1084/JEM.20200318
DO - 10.1084/JEM.20200318
M3 - Article
C2 - 32716519
AN - SCOPUS:85088848133
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 10
M1 - 20200318
ER -