The role of T follicular helper cells in T helper cell fate decisions, function, and plasticity

• Applicant: Professor Dr. Dirk Baumjohann
• Subject Area: Immunology
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252623821

• Final Report Year: 2021

Final Report Abstract

T follicular helper (Tfh) cells provide essential help to B cells for potent antibody responses. Tfh cells have also emerged as central intermediaries of other CD4+ T cell-mediated immune responses that involve the generation of certain effector and memory T helper cells. However, the precise relationships between these T helper cells remain unknown. This Emmy Noether research project aimed at dissecting the molecular and cellular requirements for the differentiation and maintenance of Tfh cells and other T helper cell subsets. We here dissected the role of the miR-17~92 cluster during Th17 cell differentiation and identified miR-18a as a potent inhibitor of Th17 cells. To address the role of miRNAs in the maintenance of Tfh cells, we developed a versatile experimental system that allowed the induced deletion of all mature miRNAs specifically in CD4+ T cells through deletion of Dgcr8, which is required for miRNA biogenesis. We found that two mouse strains containing such a CD4-CreERT2 construct differed substantially in their feasibility for these studies. Induced Dgcr8 deficiency during an ongoing immune response resulted in reduced Tfh cell frequencies and germinal centers (GCs). Besides deletion of miRNAs, we also used this system to ablate the Tfh-associated chemokine receptor Cxcr5 as well as the transcription factor Bcl6, in already differentiated Tfh cells. Induced ablation of Cxcr5 had minor effects on the function of established Tfh cells and Cxcr5-ablated cells still exhibited most features of CXCR5-positive Tfh cells. In contrast, continued Bcl6 expression was critical to maintain the GC Tfh cell phenotype and also the GC reaction. Importantly, T cell-specific Bcl6 ablation during acute viral infection resulted in transdifferentiation of established Tfh into Th1 cells, thus underlining the high degree of Tfh cell plasticity. Taken together, this project contributed to a better understanding of how Tfh cells are regulated on the molecular level and how Tfh cells contribute to T helper cell fate decisions, which could be leveraged in the future to target Tfh cells in autoimmune diseases or boost their function in infections and vaccination.

Publications

• Emerging roles for microRNAs in T follicular helper cell differentiation. Trends in Immunology 2016 May;37(5):297-309
  Maul J and Baumjohann D
  
• A Distinct Inhibitory Function for miR-18a in Th17 Cell Differentiation. The Journal of Immunology 2017 Jul 15;199(2):559-569
  Montoya MM, Maul J, Singh PB, Pua HH, Dahlström F, Wu N, Huang X, Ansel KM, Baumjohann D
  
• Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. Immunity 2017 Dec 19;47(6):1067-1082
  Essig K, Hu D, Guimaraes JC, Alterauge D, Edelmann S, Raj T, Kranich J, Behrens G, Heiseke A, Floess S, Klein J, Maiser A, Marschall S, Hrabĕ de Angelis M, Leonhardt H, Calkhoven CF, Noessner E, Brocker T, Huehn J, Krug AB, Zavolan M, Baumjohann D, Heissmeyer V
  
• MicroRNA-mediated regulation of T follicular helper and T follicular regulatory cell identity. Immunological Reviews 2019 Mar;288(1):97-111
  Maul J, Alterauge D, Baumjohann D
  
• Continued Bcl6 expression prevents the transdifferentiation of established Tfh cells into Th1 cells during acute viral infection. Cell Reports 2020 Oct 6;33(1):108232
  Alterauge D, Bagnoli JW, Dahlström F, Bradford BM, Mabbott NA, Buch T, Enard W, Baumjohann D
  
• Dynamic changes in circulating T follicular helper cell composition predict neutralizing antibody responses after yellow fever vaccination. Clinical & Translational Immunology 2020 May 13;9(5):e1129
  Huber JE, Ahlfeld J, Scheck MK, Zaucha M, Witter K, Lehmann L, Karimzadeh H, Pritsch M, Hoelscher M, von Sonnenburg F, Dick A, Barba-Spaeth G, Krug AB, Rothenfußer S, Baumjohann D
  
• Gene Dose Matters: Considerations for the Use of Inducible CD4-CreERT2 Mouse Lines. European Journal of Immunology 2020 Apr;50(4):603-605
  Zeiträg J, Alterauge A, Dahlström F, Baumjohann D
  
• Antigen-dependent multistep differentiation of T follicular helper cells and its role in SARS-CoV-2 infection and vaccination. European Journal of Immunology 2021 Jun;51(6):1325-1333
  Baumjohann D and Fazilleau N
  
• CD4+ T cells that help B cells – a proposal for uniform nomenclature. Trends in Immunology 2021 Aug;42(8):658-669
  Eisenbarth SC, Baumjohann D, Craft J, Fazilleau N, Ma CS, Tangye SG, Vinuesa CG, Linterman MA
  
• T cell-expressed microRNAs critically regulate germinal center T follicular helper cell function and maintenance in acute viral infection in mice. European Journal of Immunology 2021 Feb;51(2):408-413
  Zeiträg J, Dahlström F, Chang Y, Alterauge A, Richter D, Niemietz J, Baumjohann