Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-06, Vol.116 (26), p.12952-12957
• Main Authors: Kim, Wooseob, Kim, Eunha, Min, Hyungyu, Kim, Min Gyu, Eisenbeis, Verena B., Dutta, Amit K., Pavlovic, Igor, Jessen, Henning J., Kim, Seyun, Seong, Rho Hyun
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase - immunology; Agammaglobulinaemia Tyrosine Kinase - metabolism; Agammaglobulinemia; Agammaglobulinemia - genetics; Agammaglobulinemia - immunology; Agammaglobulinemia - pathology; Animals; Antigens; B-cell receptor; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Bacterial diseases; Biological Sciences; Bruton's tyrosine kinase; Cell activation; Disease Models, Animal; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - immunology; Genetic Diseases, X-Linked - pathology; Humans; Humoral immunity; Immune response; Immune system; Immunity; Immunity, Humoral; Immunoglobulin M; Inositol; Inositol phosphates; Kinases; Lymphocytes; Lymphocytes B; Lymphocytes T; Mice; Mice, Transgenic; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Phytic Acid - immunology; Phytic Acid - metabolism; Plasma cells; Polyphosphates; Protein-tyrosine kinase; Receptors, Antigen, B-Cell - immunology; Receptors, Antigen, B-Cell - metabolism; Signal transduction; Signal Transduction - immunology; Signaling; Tyrosine; X-linked agammaglobulinemia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1821552116

T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton’s tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as towhether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP₆) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP₆-mediated Btk regulation is more prominent in IgM⁺ plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.