6533b872fe1ef96bd12d2f8a

RESEARCH PRODUCT

EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells

Klaus RajewskyNina WettschureckStephanie GräfIlgiz A. MufazalovMorad ZayoudTanja KuhlmannSonja MoosDenise TischnerYilang TangFlorian C. KurschusAndreas W. SailerNir YogevAndrew L. CroxfordAvraham Ben-nunJulia BruttgerBettina KaltSonja M. LacherAri WaismanIsabelle ChristenSonja ReißigAndré P. HeinenKhalad KarramChristian ReichholdFlorian WankeStefano CasolaNicole IsraelJuan Zhang

subject

0301 basic medicineCD4-Positive T-LymphocytesCentral Nervous SystemMaleGPR183Cancer ResearchEncephalomyelitis Autoimmune ExperimentalOxysterolCentral nervous systemInterleukin-1betaCytochrome P450 Family 7CH25HmicrogliaAutoimmunityBiologymedicine.disease_causemultiple sclerosisInterleukin-23General Biochemistry Genetics and Molecular BiologyAutoimmunityReceptors G-Protein-Coupled03 medical and health sciencesMiceImmune systemCell MovementmedicineAnimalsEBI2lcsh:QH301-705.5MicrogliaEAEMultiple sclerosisExperimental autoimmune encephalomyelitisGPR1837α25-OHCmedicine.diseaseMice Inbred C57BLDisease Models Animal030104 developmental biologymedicine.anatomical_structurelcsh:Biology (General)ImmunologySteroid HydroxylasesTh17 CellsFemaleTh17CNSoxysterol

description

Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7{alpha},25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7{alpha},25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1{beta}), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.

yearjournalcountryeditionlanguage
2017-01-01Cell Reports
10.1016/j.celrep.2017.01.020http://dx.doi.org/10.1016/j.celrep.2017.01.020