The B7-family inducible costimulator(ICOS)activates phosphoinositide-3 kinase(PI3K)and augments calcium mobilization triggered by the T-cell receptor(TCR).We surprisingly found that the entire cytoplasmic domain of IC...The B7-family inducible costimulator(ICOS)activates phosphoinositide-3 kinase(PI3K)and augments calcium mobilization triggered by the T-cell receptor(TCR).We surprisingly found that the entire cytoplasmic domain of ICOS is dispensable for its costimulation of calcium mobilization.This costimulatory function relies on the unique transmembrane domain(TMD)of ICOS,which promotes association with the tyrosine kinase Lck.TMD-enabled Lck association is also required for p85 recruitment to ICOS and subsequent PI3K activation,and Lck underlies both the bystander and costimulatory signaling activity of ICOS.TMD-replaced ICOS,even with an intact cytoplasmic domain,fails to support T FH development or GC formation in vivo.When transplanted onto a chimeric antigen receptor(CAR),the ICOS TMD enhances interactions between T cells and antigen-presenting target cells.Therefore,by revealing an unexpected function of the ICOS TMD,our study offers a new perspective for the understanding and potential application of costimulation biology.展开更多
基金This work wasfunded in part by the Ministry of Science and Technology“973"program(Grant No.2014CB542501)the National Natural Science Foundation of China(Grant Nos.81330070,81425011,81621002,and 81761128019)+2 种基金the Tsinghua-Peking Centerfor Life SciencesThis work was also funded in part by the Bill&Melinda Gates Foundationthe Howard Hughes Medical lnstitute.
文摘The B7-family inducible costimulator(ICOS)activates phosphoinositide-3 kinase(PI3K)and augments calcium mobilization triggered by the T-cell receptor(TCR).We surprisingly found that the entire cytoplasmic domain of ICOS is dispensable for its costimulation of calcium mobilization.This costimulatory function relies on the unique transmembrane domain(TMD)of ICOS,which promotes association with the tyrosine kinase Lck.TMD-enabled Lck association is also required for p85 recruitment to ICOS and subsequent PI3K activation,and Lck underlies both the bystander and costimulatory signaling activity of ICOS.TMD-replaced ICOS,even with an intact cytoplasmic domain,fails to support T FH development or GC formation in vivo.When transplanted onto a chimeric antigen receptor(CAR),the ICOS TMD enhances interactions between T cells and antigen-presenting target cells.Therefore,by revealing an unexpected function of the ICOS TMD,our study offers a new perspective for the understanding and potential application of costimulation biology.
