Molecular regulation of T follicular helper cell maintenance by Bach2 and RankL
Final Report Abstract
T follicular helper (Tfh) cells are a specialized T cell subset that regulates the long-lived production of highly specific antibodies by B cells during the germinal center reaction. However, the transcriptional network sustaining the Tfh cell phenotype and function is still incompletely understood. In this project, we identified the transcription factor Bach2 as a central negative regulator of Tfh cells. Ectopic overexpression of Bach2 in murine Tfh cells resulted in a rapid loss of their phenotype and subsequent breakdown of the germinal center response. Low Bach2 expression levels are required to maintain high expression of the signature cytokine IL-21, the co-inhibitory receptor TIGIT and the transcriptional repressor Bcl-6. In stark contrast to the regulatory network in germinal center B cells, Bach2 in Tfh cells is not co-expressed with Bcl-6 at high levels to inhibit the antagonizing factor Blimp-1 but suppresses Bcl-6 by direct binding to the promoter. These data reveal that by replacing an activating complex of Batf and Irf-4 at the Bcl-6 promoter, Bach2 regulates the transcriptional network of Tfh cells in a different way as in germinal center B cells. In a second part of the project, we analyzed the function of the TNF superfamily member RankL (Tnfsf11), which has a unique high expression on Tfh cells, for its function in different mouse models. RankL biology is rather complex since this transmembrane molecule cannot signal directly into T cells. Instead, our data suggest that triggering of Rank on dendritic cells and macrophages induces factors which favor the survival of Tfh memory cells.
Publications
- Maintenance of T follicular helper cells in late phases of the germinal center reaction. Dissertation, Department of Biology, Chemistry und Pharmacy of Freie Universität Berlin
Annette Lahmann
- Bach2 Controls T Follicular Helper Cells by Direct Repression of Bcl-6. J Immunol (2019) 202:2229-2239
Lahmann A, Kuhrau J, Fuhrmann F, Heinrich F, Bauer L, Durek P, Mashreghi MF, Hutloff A
(See online at https://doi.org/10.4049/jimmunol.1801400) - Generation and Maintenance of T Follicular Helper Cells. Dissertation, Faculty of Natural Sciences, Christian Albrechts University Kiel
Julia Kuhrau
- Vitamin A controls the allergic response through T follicular helper cell as well as plasmablast differentiation. Allergy (2021) 76: 1109-1122
Scholz J, Kuhrau J, Heinrich F, Heinz GA, Hutloff A, Worm M, Heine G
(See online at https://doi.org/10.1111/all.14581)
