T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia

• Published in: Cellular & molecular immunology 2020-10, Vol.17 (10), p.1042-1052
• Main Authors: Xia, Simo, Liu, Xiang, Cao, Xuetao, Xu, Sheng
• Format: Article
• Language: English
• Subjects: 631/250/2152/1566; 631/250/38; Anemia; Antibodies; Aplastic anemia; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Bone marrow; Bruton's tyrosine kinase; Cell activation; Cell differentiation; Cell proliferation; Immunology; Kinases; Lymphocytes; Lymphocytes B; Lymphocytes T; Medical Microbiology; Microbiology; Pathogenesis; Protein-tyrosine kinase; T cell receptors; Vaccine
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/s41423-019-0270-9

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.