The role of Bruton’s tyrosine kinase(BTK)in BCR signaling is well defined,and BTK is involved in B-cell development,differentiation,and malignancies.However,the expression of Btk in T cells and its role in T-cell fun...The role of Bruton’s tyrosine kinase(BTK)in BCR signaling is well defined,and BTK is involved in B-cell development,differentiation,and malignancies.However,the expression of Btk in T cells and its role in T-cell function remain largely unknown.Here,we unexpectedly found high expression and activation of BTK in T cells.Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure(BMF)in aplastic anemia.Mechanistically,BTK is activated after TCR engagement and then phosphorylates PLCγ1,thus promoting T-cell activation.Treatment with acalabrutinib,a selective BTK inhibitor,decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia.Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia,providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.展开更多
基金supported by the National Key Basic Research Program of China(2015CB964403)the National Key R&D Program of China(2018YFA0507401,2017YFA0104402)+1 种基金the National Natural Science Foundation of China(81471569,31870910)the Shanghai Committee of Science and Technology(15QA1404700).
文摘The role of Bruton’s tyrosine kinase(BTK)in BCR signaling is well defined,and BTK is involved in B-cell development,differentiation,and malignancies.However,the expression of Btk in T cells and its role in T-cell function remain largely unknown.Here,we unexpectedly found high expression and activation of BTK in T cells.Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure(BMF)in aplastic anemia.Mechanistically,BTK is activated after TCR engagement and then phosphorylates PLCγ1,thus promoting T-cell activation.Treatment with acalabrutinib,a selective BTK inhibitor,decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia.Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia,providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.
