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

26 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

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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