We are thrilled to see our tour-de-force on the role of TGF-β and c-Maf in Tfh/Th17 cell differentiation now published in Science Immunology (freely accessible through our list of Publications):
TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf
Chang Y#, Bach L#, Hasiuk M, Wen L, Elmzzahi T, Tsui C, Gutiérrez-Melo N, Steffen T, Utzschneider DT, Raj T, Jost PJ, Heink S, Cheng J, Burton OT, Zeiträg J, Alterauge D, Dahlström F, Becker JC, Kastl M, Symeonidis K, van Uelft M, Becker M, Reschke S, Krebs S, Blum H, Abdullah Z, Paeschke K, Ohnmacht C, Neumann C, Liston A, Meissner F, Korn T, Hasenauer J, Heissmeyer V, Beyer M, Kallies A, Jeker LT, Baumjohann D*.
Science Immunology. 2024 Mar;9(93):eadd4818. doi: 10.1126/sciimmunol.add4818. #Equal contribution *Corresponding author
We found that TGF-β robustly induced protein expression of the Tfh-associated hallmark chemokine receptor CXCR5 and the transcription factor Bcl6 in anti-CD3/CD28-activated murine CD4+ T cells cultured under TGF-β-containing Tfh-polarizing conditions in vitro, but not under previously published Tfh-like conditions that include neutralizing antibodies against TGF-β. TGF-β-induced CXCR5+ Tfh cells were functional, as they migrated towards gradients of its ligand CXCL13 and provided critical help to B cells in vitro, similar to in vivo-generated Tfh cells. Dissection of the TGF-β-induced molecular pathways by utilizing CD4+ T cells from various conditional gene knock-out mouse strains, bulk RNA-seq, single-cell RNA-seq, proteomics, CRISPR/Cas9 for gene ablation in naive CD4+ T cells, and in vivo data, revealed that CXCR5 expression was independent of Bcl6 but depended on c-Maf. We provide experimental evidence for c-Maf acting as a switch factor of Tfh vs. Th17 cell fate decisions in vitro and in vivo. Importantly, classical TGF-β-induced Th17 cultures also yielded separate CXCR5+ and IL-17A-producing cells, thus highlighting shared and distinct cell fate trajectories of Tfh and Th17 cells. This is relevant, as in vitro-generated Th17 cells have been previously described as potent B cell helpers. These data also suggest that murine and human Tfh cell differentiation may not be as different as previously believed, as TGF-β is known to be a Tfh-promoting factor for human Tfh cells.
Congratulations to the first authors Yinshui and Luisa, and to the whole team! We are very grateful to the many collaborators within the Cluster of Excellence ImmunoSensation2 and around the world.
Four different bulk-RNA-seq and one single-cell-RNA-seq data sets accompany the paper as a hopefully valuable resource and can be assessed through GEO: GSE198370, GSE198374, GSE197425, GSE243257, and GSE197842.