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.
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.
Weber, J.P., Fuhrmann, F., and Hutloff, A. (2012). T-follicular helper cells survive as long-term memory cells. Eur J Immunol 42, 1981-1988.
Lischke, T., Hegemann, A., Gurka, S., Vu Van, D., Burmeister, Y., Lam, K.P., Kershaw, O., Mollenkopf, H.J., Mages, H.W., Hutloff, A., and Kroczek, R.A. (2012). Comprehensive analysis of CD4+ T cells in the decision between tolerance and immunity in vivo reveals a pivotal role for ICOS. J Immunol 189, 234-244.
Burmeister, Y., Lischke, T., Dahler, A.C., Mages, H.W., Lam, K.P., Coyle, A.J., Kroczek, R.A., and Hutloff, A. (2008). ICOS controls the pool size of effector-memory and regulatory T cells. J Immunol 180, 774-782.
Hutloff, A., Büchner, K., Reiter, K., Baelde, H.J., Odendahl, M., Jacobi, A., Dörner, T., and Kroczek, R.A. (2004). Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus. Arthritis Rheum 50, 3211-3220.
Beier, K.C., Hutloff, A., Löhning, M., Kallinich, T., Kroczek, R.A., and Hamelmann, E. (2004). Inducible costimulator-positive T cells are required for allergen-induced local B-cell infiltration and antigen-specific IgE production in lung tissue. J Allergy Clin Immunol 114, 775-782.
Löhning, M.*, Hutloff, A.*, Kallinich, T., Mages, H.W., Bonhagen, K., Radbruch, A., Hamelmann, E., and Kroczek, R.A. (2003). Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J Exp Med 197, 181-193.
Grimbacher, B.*, Hutloff, A.*, Schlesier, M., Glocker, E., Warnatz, K., Dräger, R., Eibel, H., Fischer, B., Schaffer, A.A., Mages, H.W., Kroczek, R.A.*, and Peter, H.H*. (2003). Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4, 261-268.
Hutloff, A., Dittrich, A.M., Beier, K.C., Eljaschewitsch, B., Kraft, R., Anagnostopoulos, I., and Kroczek, R.A. (1999). ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263-266.