Prof. Dr. Jumaa Hassan
Institut für Immunologie
The role of PI3-kinase signaling in the selection and survival of B cells
The generation of long-lived memory B cells ensures persistent antibody production and protection from recurrent infections by pathogens. Our project is aimed at better understanding the molecular mechanisms that regulate B cell differentiation and selection and the role of PI3K signalling and downstream elements including PTEN and FoxO1 in these processes. By crossing knock-ins for HC and LC of the 3-83 BCR into the background of loxP-flanked genes for PTEN and FoxO1, we could show that PTEN is essential for receptor editing and that PTEN-deficient B cells show deregulated activation of factors associated with terminal differentiation such as Blimp-1 leading to increased amounts of autoreactive IgM but not IgG. Our results also suggested that IgM possesses a reduced activation threshold and can therefore be readily activated by low-valence antigen. This characteristic feature of IgM provides developing B cells with high sensitivity for responding to soluble autoantigens and seems to be important for the development and selection of B cells. To identify the mechanisms by which PTEN and FoxO1 regulate early B cell development, we screened for genes that link BCR activation to PTEN and, thus, to the regulation of PI3-K activity. We identified RhoA, a Rho family member of small GTPases, as essential factor for PTEN and FoxO1 function in B cells. In fact, similar to conditional inactivation of PTEN and FoxO1, B cell-specific inactivation of RhoA expression at the pro-B cell stage leads to complete block of B cell development. Inactivation of RhoA in the periphery using CD21-cre transgenic mice results in the development of autoreactive B cells and increased amounts of autoreactive antibodies in the serum of aging female mice. Interestingly, RhoA-deficient B cells show increased calcium mobilization after anti-BCR treatment. The characterization of RhoA-regulated PI3K signalling and the autoimmune phenotype of the RhoA-deficient mature B cells as well as the role of RhoA in human autoimmune diseases are the main focus of this funding period.
Abdelrasoul, H., Vadakumchery, A., Werner, M., Lenk, L., Khadour, A., Young, M., El Ayoubi, O., Vogiatzi, F., Krämer, M., Schmid, V., Chen, Z., Yousafzai, Y., Cario, G., Schrappe, M., Müschen, M., Halsey, C., Mulaw, M.A., Schewe, D.M., Hobeika, E., Alsadeq, A., and Jumaa, H. (2020). Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Nat. Comm. 11, 3194. doi: 10.1038/s41467-020-16927-w.
Maity PC, ..., Mei H, Ghia P, Kotta K, Stamatopoulos K, Wardemann H, Zucchetto A, Chiorazzi N, Gattei V, Stilgenbauer S, Veelken H, and Jumaa H. (2020). IGLV3-21*01 is an inherited risk factor for CLL through acquisition of a single point mutation enabling autonomous BCR signaling. Proc. Natl. Acad. Sci. USA 117, 4320-4327.
Setz, C.S., Khadour, A., Renna, V., Iype, V., Gentner, E., He, X., Datta, M., Young, M., Nitschke, L., Wienands, J., Maity, P.C., Reth, M., and Jumaa, H. (2019). Pten controls B cell responsiveness and germinal center reaction by regulating the expression of IgD BCR. EMBO J. doi: 10.15252/embj.2018100249.
Iype, J., Datta, M., Khadour, A., Übelhart, R., Nicolò, A., Rollenske, T., Dühren-von Minden, M., Wardemann, H., Maity, P.C., and Jumaa, H. (2019). Differences in self-recognition between secreted antibody and membrane-bound B cell antigen receptor. J. Immunol. 202, 1417-1427.
Setz, C.S., Hug, E., Khadour, A., Abdelrasoul, H., Bilal, M., Hobeika, E., and Jumaa, H. (2018). PI3K-Mediated Blimp-1 Activation Controls B Cell Selection and Homeostasis. Cell Rep. 24, 391-405.
Imkeller, K., Scally, S., Bosch, A., Martí, G., Costa, G., Triller, G., Murugan, R., Renna, V., Jumaa, H., Kremsner, P., Sim, B., Hoffman, S., Mordmüller, B., Levashina, E., Julien, J., and Wardemann, H. (2018). Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope. Science 360, 1358-62.
Becker, M., Hobeika, E., Jumaa, H., Reth, M., and Maity, P.C. (2017). CXCR4 signaling and function require the expression of the IgD-class B-cell antigen receptor. Proc. Natl. Acad. Sci. USA 114, 5231-5236.
Dolezal, E., Infantino, S., Drepper, F., Börsig, T., Singh, A., Wossning, T., Fiala, G.J., Minguet, S., Warscheid, B., Tarlinton, D.M., Jumaa, H., Medgyesi, D., and Reth, M. (2017). The BTG2-PRMT1 module limits pre-B cell expansion by regulating the CDK4-Cyclin-D3 complex. Nat. Immunol. 18, 911-920.
Hobeika, E., Maity, P.C., Jumaa, H. (2016) Control of B cell responsiveness by the isotype and structural elements of the antigen receptor. Trends Immunol.37: 310-320.
Shojaee. S., Chan, L.N., Buchner, M., Cazzaniga, V., Cosgun, K.N., Geng, H., Qiu, Y.H., von Minden, M.D., Ernst, T., Hochhaus, A., Cazzaniga, G., Melnick, A., Kornblau, S.M., Graeber, T.G., Wu, H., Jumaa, H., Müschen, M. (2016) Nat Med. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med. 22:379-87.
Übelhart, R., Jumaa, H. (2015). Autoreactivity and the positive selection of B cells. Eur J Immunol. 45:2971-2977.
Flemming, A., Huang, Q.Q., Jin, J.P., Jumaa, H., Herzog, S. (2015) A conditional knockout mouse model reveals that calponin-3 is dipensible for early B cell development. PLoS One. 10(6):e0128385.
Maity, P.C., Blount, A., Jumaa, H., Ronneberger, O., Lillemeier, B.F., Reth, M. (2015) B cell antigen receptors of IgM and IgD classes are clustered in different protein islands that are altered during B cell activation. Sci Signal. 8(394):ra93.
Kumar, R., Bach, M.P., Mainoldi, F., Maruya, M., Kishigami, S., Jumaa, H., Wakayama, T., Kanagawa, O., Fagarasan, S., Casola, S. (2015) Antibody repertoire diversification through VH gene replacement in mice cloned from an IgA plasma cell. Proc Natl Acad Sci U S A. 112:450-457.
Übelhart, R., Hug, E., Bach, M.P., Wossning, T., Dühren-von Minden, M., Horn, A.H., Tsiantoulas, D., Kometani, K., Kurosaki, T., Binder, C.J., Sticht, H., Nitschke, L., Reth, M., Jumaa, H. (2015) Responsiveness of B cells is regulated by the hinge region of IgD. Nat Immunol. 16:534-543.