Dr. rer. nat. Andreas Hutloff
Deutsches Rheuma-Forschungszentrum Berlin
Germinal center-like B cells in inflamed tissues
B cell activation and differentiation normally takes place in secondary lymphoid organs. However, under inflammatory conditions, B cells are frequently found in inflamed non-lymphoid tissues where they substantially contribute to tissue destruction by production of antibodies and pro-inflammatory chemokines. We now could show that B cells in the tissue do not only exert effector functions but that the inflamed tissue is a site of active B cell differentiation taking place outside secondary or tertiary lymphoid tissues.
We have developed a murine airway inflammation model which allows to track and analyze antigen-specific B and T cells simultaneously in lung-draining lymph node and inflamed lung tissue. In the inflamed lung, we identified two novel B cell populations of either Bcl-6+ germinal center-like or T-bet+ CXCR3+ inflammatory B cells located outside ectopic lymphoid tissue. Our data indicate that germinal center-like B cells locally differentiate in contact with follicular helper-like T cells, hypermutate their B cell receptor, and give rise to local antibody-producing cells.
In this project, we will further define the phenotype and function of tissue-infiltrating B cells in comparison to classical germinal center B cells in secondary lymphoid organs. To answer the question how B cell differentiation can take place outside of the ordered structure of the germinal center, we will analyze the composition and micro-environment of lung infiltrates. To track the migratory behavior and the interaction of lung-infiltrating B cells with other cell types, a micro-bronchoscopic in vivo imaging technique will be established. We will also functionally analyze factors like T-bet, CXCR3, and different chemokines regarding their role in B cell migration into the tissue, generation of a local inflammatory micro-environment, and for the generation of germinal center-like B cells in the tissue.
Since B cells in inflamed tissues represent a significant proportion of all antigen-specific B cells, a better understanding of their commonalities and differences compared to B cells in secondary lymphoid organs will be important for all B cell-targeted therapies.
Scholz, J., Kuhrau, J., Heinrich, F., Heinz, G.A., Hutloff, A.*, Worm, M.*, and Heine, G.* (2020). Vitamin A controls the allergic response through T follicular helper cell as well as plasmablast differentiation. Allergy in press. doi: 10.1111/all.14581. * equal contribution
Lino, A.C., Dang, V.D., Lampropoulou, V., Welle, A., Joedicke, J., Pohar, J., Simon, Q., Thalmensi, J., Baures, A., Fluhler, V., Sakwa, I., Stervbo, U., Ries, S., Jouneau, L., Boudinot, P., Tsubata, T., Adachi, T., Hutloff, A., Dorner, T., Zimber-Strobl, U., de Vos, A.F., Dahlke, K., Loh, G., Korniotis, S., Goosmann, C., Weill, J.C., Reynaud, C.A., Kaufmann, S.H.E., Walter, J., and Fillatreau, S. (2018). LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Immunity 49, 120-133.e129.
Ugolini, M., Gerhard, J., Burkert, S., Jensen, K.J., Georg, P., Ebner, F., Volkers, S.M., Thada, S., Dietert, K., Bauer, L., Schafer, A., Helbig, E.T., Opitz, B., Kurth, F., Sur, S., Dittrich, N., Gaddam, S., Conrad, M.L., Benn, C.S., Blohm, U., Gruber, A.D., Hutloff, A., Hartmann, S., Boekschoten, M.V., Muller, M., Jungersen, G., Schumann, R.R., Suttorp, N., and Sander, L.E. (2018). Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses. Nat. Immunol. 19, 386-396.
Vu Van, D., Beier, K.C., Pietzke, L.J., Al Baz, M.S., Feist, R.K., Gurka, S., Hamelmann, E., Kroczek, R.A., and Hutloff, A. (2016). Local T/B cooperation in inflamed tissues is supported by T follicular helper-like cells. Nat Commun 7, 10875.
Weber, J.P., Fuhrmann, F., Feist, R.K., Lahmann, A., Al Baz, M.S., Gentz, L.J., Vu Van, D., Mages, H.W., Haftmann, C., Riedel, R., Grün, J.R., Schuh, W., Kroczek, R.A., Radbruch, A., Mashreghi, M.F., and Hutloff, A. (2015). ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2. J Exp Med 212, 217-233.
Pratama, A., Srivastava, M., Williams, N.J., Papa, I., Lee, S.K., Dinh, X.T., Hutloff, A., Jordan, M.A., Zhao, J.L., Casellas, R., Athanasopoulos, V., and Vinuesa, C.G. (2015). MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat Commun 6, 6436.