Selection of B cells in germinal centres
Most antibody responses involve affinity maturation. This process occurs in germinal centres (GCs), microanatomical structures in lymphoid tissues where B lymphocytes mutate and mature their immunoglobulin V-genes. Affinity maturation is thought to be achieved by Darwinian evolution with repeated cycles of Ig hypermutation followed by B cell interaction with the antigen that is on follicular dendritic cells. This is then followed by stimulation from follicular T helper cells. We are studying how antigen, antibodies, T cells and other accessory cells in germinal centre interact with B cells and provide stimulation or barriers that lead to selection of higher affinity B cells. Main focus of this work is to understand the action of vaccines, and to understand processes that become defunctional during ageing.
Regulation of immunoglobulin class switching and plasma cell differentiation
B cells not only mutate their antibody genes after contact with antigen, they also rearrange these genes to produce antibody switch variants with same specificity, but different function. This process is called immunoglobulin class switching and happens in B cells at different stages and in different microanatomical compartments during an antibody response. The end product of B cell differentiation is the plasma cell – a cellular factory specialised in producing large amounts of antibody. Similar microenvironments and signals to the ones that induce immunoglobulin class switching also regulate plasma cell differentiation.
We are trying to understand the molecular signals that lead to these processes and the cellular interactions that provide signals for immunoglobulin class switching or plasma cell differentiation.
T helper lymphocyte differentiation
T helper cells are the main cells that interact with B cells and regulate antibody responses, having a role not only in the initiation of B cell differentiation, but also for long term immunological memory. We are interested in the differentiation of specialized subsets of T cells regulating B cell differentiation, and in the development and distribution of memory T cells throughout different microanatomical compartments.
Figge, M. T., A. Garin, M. Gunzer, M. Kosco-Vilbois, K.-M. Toellner, M. Meyer-Hermann
Deriving a germinal center lymphocyte migration model from two-photon data
Journal of Experimental Medicine, 2008, 205, 3019-3029
Marshall, J. L., Y. Zhang, L. Pallan, M.-C. Hsu, M. Khan, A. Cunningham, I. C. M. MacLennan, K.-M. Toellner Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts
European Journal of Immunology, 2011, 41, 3506-3512.
Meyer-Hermann, M., E. Mohr, N. Pelletier, Y. Zhang, G. D. Victora, K.-M. Toellner. A novel theory of germinal center B cell selection, division, and exit
Cell Reports, 2012, 26, 162-174.
Zhang Y., M. Meyer-Hermann, L. George, M. T. Figge, M. Khan, M. Goodall, S. P. Young, A. Reynolds, F. Falciani, A. Waisman, C. A. Notley, M. R. Ehrenstein, M. Kosco-Vilbois, K.-M. Toellner. Germinal centre B cells govern their own fate via antibody feedback
Journal of Experimental Medicine, 2013, 210, 457-464
Stamm, C., J. Barthelmann, N. Kunz, K.-M. Toellner, J. Westermann, K. Kalies. Dose-dependent Induction of Murine Th1/Th2 Responses to Sheep Red Blood Cells Occurs in Two Steps: Antigen Presentation during Second Encounter Is Decisive
PLOS One, 2013, 8(6): e67746.
Caganova, M., C. Carrisi, F. Mainoldi, L. George, F. Alberghini, M. Ponzoni, T. Nojima, C. Doglioni, D. Kitamura, K.-M. Toellner, I. Su, S. Casola. Regulation of the germinal center B-cell program by the histone H3 lysine-27 methyltransferase Ezh2
Journal of Clinical Investigation, 2013, 123, 5009-5022
Toellner, K.-M. Cognate interactions: extrafollicular IL-4 drives germinal centre reactions, a new role for an old cytokine
European Journal of Immunology, 2014, 44, 1917-1920
Zhuang, X., F. Ahmed, Y. Zhang, J. C. Steele, N. M. Steven, V. L. Heath, K.-M. Toellner, R. Bicknell. Vaccination against the tumour endothelial marker Robo4 inhibits angiogenesis and tumour growth
Angiogenesis, 2015, 18(1):83-95