A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation

Melanie S. Vacchio, Thomas Ciucci, Yayi Gao, Masashi Watanabe, Mariah Balmaceno-Criss, Mitchell T. McGinty, Allan Huang, Qi Xiao, Cameron McConkey, Yongmei Zhao, Jyoti Shetty, Bao Tran, Marion Pepper, Golnaz Vahedi, Marc K. Jenkins, Dorian B. McGavern, Rémy Bosselut

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

The generation of high-affinity neutralizing antibodies, the objective of most vaccine strategies, occurs in B cells within germinal centers (GCs) and requires rate-limiting "help" from follicular helper CD4 + T (Tfh) cells. Although Tfh differentiation is an attribute of MHC II-restricted CD4 + T cells, the transcription factors driving Tfh differentiation, notably Bcl6, are not restricted to CD4 + T cells. Here, we identified a requirement for the CD4 +-specific transcription factor Thpok during Tfh cell differentiation, GC formation, and antibody maturation. Thpok promoted Bcl6 expression and bound to a Thpok-responsive region in the first intron of Bcl6. Thpok also promoted the expression of Bcl6-independent genes, including the transcription factor Maf, which cooperated with Bcl6 to mediate the effect of Thpok on Tfh cell differentiation. Our findings identify a transcriptional program that links the CD4 + lineage with Tfh differentiation, a limiting factor for efficient B cell responses, and suggest avenues to optimize vaccine generation.

Original languageEnglish (US)
Pages (from-to)465-478.e6
JournalImmunity
Volume51
Issue number3
DOIs
StatePublished - Sep 17 2019

Bibliographical note

Funding Information:
We thank T.-A. Lewis, E. Castro, and H. Kwak for expert animal care and genotyping; Y. Belkaid, J. Zhu, J. O’Shea, Ming Li, R. Ahmed, and the NIH tetramer facility for mice and reagents; Maggie Cam (CCR Bioinformatics Core), the CCR Flow Cytometry Core, the CCR Confocal Microscopy Core Facility, and the NIH high-performance computing cluster for assistance; and J. Ashwell, Y. Belkaid, R. Hodes, P. Love, and J. Zhu for reading the manuscript. This work benefited from data assembled by the Immgen Consortium. Supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH .

Publisher Copyright:
© 2019

Keywords

  • Bcl6
  • CD4 T cells
  • Maf
  • Thpok
  • follicular helper T cells
  • germinal center reaction
  • Gene Expression Regulation/immunology
  • Mice, Inbred C57BL
  • T-Lymphocytes, Helper-Inducer/immunology
  • B-Lymphocytes/immunology
  • Proto-Oncogene Proteins c-bcl-6/immunology
  • Animals
  • CD4-Positive T-Lymphocytes/immunology
  • Cell Differentiation/immunology
  • Lymphocyte Activation/immunology
  • Transcription Factors/immunology
  • Female
  • Transcription, Genetic/immunology
  • Mice
  • Antibodies, Neutralizing/immunology
  • Germinal Center/immunology
  • Proto-Oncogene Proteins c-maf/immunology

PubMed: MeSH publication types

  • Research Support, N.I.H., Intramural
  • Journal Article
  • Research Support, N.I.H., Extramural

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