CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation

Tomohiro Kaji, Atsushi Hijikata, Akiko Ishige, Toshimori Kitami, Takashi Watanabe, Osamu Ohara, Noriyuki Yanaka, Mariko Okada, Michiko Shimoda, Masaru Taniguchi, Toshitada Takemori

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Memory CD4+ T cells promote protective humoral immunity; however, how memory T cells acquire this activity remains unclear. This study demonstrates that CD4+ T cells develop into antigen-specific memory T cells that can promote the terminal differentiation of memory B cells far more effectively than their naive T-cell counterparts. Memory T cell development requires the transcription factor B-cell lymphoma 6 (Bcl6), which is known to direct T-follicular helper (Tfh) cell differentiation. However, unlike Tfh cells, memory T cell development did not require germinal center B cells. Curiously, memory T cells that develop in the absence of cognate B cells cannot promote memory B-cell recall responses and this defect was accompanied by down-regulation of genes associated with homeostasis and activation and up-regulation of genes inhibitory for T-cell responses. Although memory T cells display phenotypic and genetic signatures distinct from Tfh cells, both had in common the expression of a group of genes associated with metabolic pathways. This gene expression profile was not shared to any great extent with naive T cells and was not influenced by the absence of cognate B cells during memory T cell development. These results suggest that memory T cell development is programmed by stepwise expression of gatekeeper genes through serial interactions with different types of antigen-presenting cells, first licensing the memory lineage pathway and subsequently facilitating the functional development of memory T cells. Finally, we identified Gdpd3 as a candidate genetic marker for memory T cells.

Original languageEnglish (US)
Pages (from-to)267-282
Number of pages16
JournalInternational Immunology
Issue number6
StatePublished - Jun 24 2016


  • Bcl6 (b-cell lymphoma 6)
  • CD4 memory T-cell development
  • Cognate interaction with non-GC B cells
  • Memory B-cell recall response
  • Stepwise transcriptional regulation
  • T-follicular helper cells

ASJC Scopus subject areas

  • Immunology


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