acp-196 and Anemia--Aplastic

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.

Topics: Acute Disease; Agammaglobulinaemia Tyrosine Kinase; Anemia, Aplastic; Animals; Benzamides; Bone Marrow; Cell Proliferation; Graft vs Host Disease; Lymphocyte Activation; Mice, Inbred BALB C; Mice, Inbred C57BL; Phospholipase C gamma; Phosphorylation; Pyrazines; Receptors, Antigen, T-Cell; T-Lymphocytes