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- W4313356007 abstract "Abstract The interaction between inducible costimulator (ICOS) and its ligand (ICOSL) is essential for proper T-dependent humoral immune responses, especially follicular helper T cell (TFH) development. We have demonstrated that A Disintegrin and Metalloproteinase 10 (ADAM10) is the primary and physiological sheddase of ICOSL. Using an in vivo system in which ADAM10 is deleted only on B cells (ADAM10B−/−) leads to high ICOSL levels which in turn causes downregulation of surface T cell ICOS expression through internalization of ICOS. In an unimmunized state, ICOS is internalized in ADAM10B−/−mice and is preferentially shuttled to the lysosomal compartment for degradation. We have recapitulated these findings in an in vitro system, showing that upon ligation, ICOS is rapidly internalized and is shuttled to endosomal recycling or lysosomal degradation, depending on availability of TCR costimulation. Thus, elevated ICOSL in the absence of TCR stimulation results in loss of ICOS and recapitulates the phenotype of an ICOS knockout with severe defects in T follicular helper (TFH) development and Th2 polarization, as well as enhanced Th1 and Th17 immune responses. Blockade of ICOSL in ADAM10B−/−mice rescues T cell ICOS surface expression and restores both TFH numbers and antibody production. Overall, we propose a novel regulation of the ICOS:ICOSL axis, with ADAM10 directly regulating ICOSL which in turn regulates ICOS levels." @default.
- W4313356007 created "2023-01-06" @default.
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- W4313356007 date "2017-05-01" @default.
- W4313356007 modified "2023-09-23" @default.
- W4313356007 title "ADAM10 regulates the ICOS:ICOSL axis" @default.
- W4313356007 doi "https://doi.org/10.4049/jimmunol.198.supp.152.15" @default.
- W4313356007 hasPublicationYear "2017" @default.
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