Toellner Group

Toellner Group
Toellner Group

Research Summary

We aim to understand the biology of the immune system response by studying lymphocytes that are responding to vaccination or infection. Our work advances our understanding of antibody protection, auto-immunity and the ageing immune system. In particular we study the processes that happen in lymph nodes and other lymphoid tissues, when B cells interact with incoming antigens to produce antibody responses specific to these antigens.

Understanding how vaccines work, how we become immune in the long term, and how the immune system is triggered to produce highly specific antibodies may lead to better understanding on how to improve vaccines and long-term immunity to pathogens. Understanding the biology of antibody responses is relevant for a number of reasons. Vaccination inducing long term antibody-mediated protection to a number of pathogens is an important health intervention, providing the general population with immunity to old and new infectious agents. Vaccination is also a necessary first step in the generation of new monoclonal antibody drugs and therefore of interest for biotech industry.

Occasionally, our immune system can spontaneously start antibody responses against parts of our own body. Understanding how such autoimmune disease is triggered, is important for a range of different autoimmune diseases. Particularly the ageing immune system has trouble regulating the antibody response: vaccination in aged people to many vaccines is not working as efficiently as in young people, and autoimmunity becomes more prevalent.

We study antibody responses of B cells by following their migration and differentiation in lymphoid tissues. Developing antibody responses involve complex and repeated interactions between B cells and other accessory cells. While they interact, cells exchange signals that activate, regulate, and select cells on both sides of these interactions. We study these responses in mice that have genetic deletions of genes involved in these interactions, or that express fluorescent reporter genes that label specific cells while they undergo interactions.

Our main interests are signals that induce activation and selection of B cells, feedback on Tfh responses, the roles of antibody in selecting B cells, antigen entry and interactions of B cells with macrophages, the regulation of antibody affinity maturation, signals inducing the generation of antibody forming cells, and the functions and roles of memory B cells.

Latest Publications

Petersone L, Wang CJ, Edner NM, Fabri A, Nikou SA, Hinze C, Ross EM, Ntavli E, Elfaki Y, Heuts F, Ovcinnikovs V, Rueda Gonzalez A, Houghton LP, Li HM, Zhang Y, Toellner KM, Walker LSK Immunology

Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.

+view abstract The Journal of experimental medicine, PMID: 37466652

Zhang Y, Garcia-Ibanez L, Ulbricht C, Lok LSC, Pike JA, Mueller-Winkler J, Dennison TW, Ferdinand JR, Burnett CJM, Yam-Puc JC, Zhang L, Alfaro RM, Takahama Y, Ohigashi I, Brown G, Kurosaki T, Tybulewicz VLJ, Rot A, Hauser AE, Clatworthy MR, Toellner KM Immunology

Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (B) and find that many B cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, B cells may exit the lymph node to enter distant tissues, while some B cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibits the recycling of B cells and results in less efficient adaption to antigenic variation. Our findings thus suggest that the recycling of antigen variant-specific B cells and transport of antigen back to GC may support affinity maturation to antigenic drift.

+view abstract Nature communications, PMID: 35513371

Yam-Puc JC, Zhang L, Maqueda-Alfaro RA, Garcia-Ibanez L, Zhang Y, Davies J, Senis YA, Snaith M, Toellner KM Immunology

It is still not clear how B cell receptor (BCR) signaling intensity affects plasma cell (PC) and germinal center (GC) B cell differentiation. We generated Cγ1 Ptpn6 mice where SHP-1, a negative regulator of BCR signaling, is deleted rapidly after B cell activation. Although immunization with T-dependent antigens increased BCR signaling, it led to PC reduction and increased apoptosis. Dependent on the antigen, the early GC B cell response was equally reduced and apoptosis increased. At the same time, a higher proportion of GC B cells expressed cMYC, suggesting GC B cell-Tfh cell interactions may be increased. GC B cell numbers returned to normal at later stages, whereas affinity maturation was suppressed in the long term. This confirms that BCR signaling not only directs affinity-dependent B cell selection but also, without adequate further stimulation, can inflict cell death, which may be important for the maintenance of B cell tolerance.

+view abstract iScience, PMID: 33532715

Group Members

Kai-Michael Toellner

Group Leader

Amani Al-Zahrani

Visiting PhD Student

Muhammet Ali Kara

PhD Student

Yang Zhang

Visiting Scientist