Prof. Dr. David Vöhringer
Infektionsbiologische Abteilung am Institut für
Medizinische Mikrobiologie, Immunologie & Hygiene
STAT6-regulated B Cell responses during Helminth infection
Helminth infections affect more than 2 billion people and cause major socio-economic problems in developing countries. The immunologic effector mechanisms that control the infection are not well understood and vaccines are not available yet. Helminths and allergens elicit a type 2 immune response which is characterized by high IgE levels and eosinophilia. During the first funding period, we observed that IL-4-induced activation of the transcription factor STAT6 in B cells is required for germinal center formation during type 2 immune responses. We identified new STAT6-regulated proteins in B cells that will be characterized in aim 1 of the current funding period. We further generated mice which express a constitutively active form of STAT6 in B cells. In aim 2, we will first characterize B cell development under steady-state conditions and then challenge the mice by infection with the helminth Nippostrongylus brasiliensis. In addition, we will investigate whether STAT6-regulated proteins modulate the humoral immune response during infection with the Lymphocytic Choriomeningitis Virus (LCMV). In the 3rd aim, we will investigate the germinal center response and the development of memory B cells using B cell fate mapping. Therefore, we will use AIDCreERT2_R26-tdtomato mice where we can label a cohort of germinal center B cells during a first infection with helminths or LCMV by injection of tamoxifen and follow their fate over time. We will further use AIDCreERT2_R26-Confetti mice to investigate the clonal distribution of germinal center B cells during helminth or LCMV infection. The Confetti allele encodes four different fluorescent proteins that can be expressed randomly upon Cre-recombination. In collaboration with Anja Hauser and Raluca Niesner, we will use 2-photon microscopy to visualize the 3D structure of germinal centers and determine the distribution of colors within individual germinal centers. In collaboration with Niklas Engels and Jürgen Wienands, we will continue to characterize the IgE response in vivo using mice that lack the cytoplasmic tail of IgE or have a point mutation in the ITT motif.
Fig. 1. In this project, we study the humoral immune response to the helminth Nippostrongylus brasiliensis. Germinal center formation is dependent on T cell-derived IL-4/IL-13 and STAT6 expression in B cells. We will characterize STAT6-regulated proteins, study the germinal center formation and investigate the regulation of IgE responses.
Mokada-Gopal, L., Boeser, A., Lehmann, C. H. K., Drepper, F., Dudziak, D., Warscheid, B., and Voehringer, D. (2017). Identification of novel STAT6-regulated proteins in mouse B cells by comparative transcriptome and proteome analysis. J Immunol 198:3737
Turqueti-Neves, A., Otte, M., Schwartz, C., Lindner, C., Pabst, O., Yu, P., and Voehringer, D. (2015). The extrafollicular domains of IgG1 and T cell-derived IL-4/IL-13 are critical for the polyclonal memory IgE response in vivo. PLoS Biology 13:e1002290.
Schwartz, C., Turqueti-Neves, A., Hartmann, S., Yu, P., Nimmerjahn, F., and Voehringer, D. (2014). Basophil-mediated Protection against Gastrointestinal Helminths Requires IgE-induced Cytokine Secretion. Proc Natl Acad Sci USA 111:E5169-77
Turqueti-Neves, A., Otte, M., Prazeres da Costa, O., Höpken, U.E., Lipp, M., Buch, T., and Voehringer, D. (2014). B-cell-intrinsic STAT6 controls germinal center formation. Eur. J. Immunol. doi: 10.1002/eji.201344203
Brachs, S., Turqueti-Neves, A., Stein, M., Reimer, D., Brachvogel, B., Bösl, M., Winkler, T., Voehringer, D., Jäck, H.-M., and Mielenz, D. (2014). Swiprosin-1/EFhd2 limits germinal center responses and humoral type 2 immunity. Eur. J. Immunol. 44:3206-3219
Ohnmacht, C., Schwartz, C., Schiedewitz, I., Naumann, R. and Voehringer, D. (2010). Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 33, 364-374.
Ohnmacht, C., and Voehringer, D. (2009). Basophil effector function and homeostasis during helminth infection. Blood 113, 2816-2825.
Reese, T. A., Liang, H.-E., Huang, X., Tager, A.M., Luster, A.D., van Rooijen, N., Voehringer, D., and Locksley, R.M. (2007). Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92-96.