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 journalArticle

Abstract

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
Volume28
Issue number6
DOIs
StatePublished - Jun 24 2016

Fingerprint

Mental Competency
T-Lymphocytes
Genes
B-Lymphocytes
Helper-Inducer T-Lymphocytes
Germinal Center
B-Cell Lymphoma
Antigen-Presenting Cells
Licensure
Humoral Immunity
Metabolic Networks and Pathways
Genetic Markers
Transcriptome
Cell Differentiation
Homeostasis
Transcription Factors
Up-Regulation
Down-Regulation

Keywords

  • 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

Cite this

CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation. / Kaji, Tomohiro; Hijikata, Atsushi; Ishige, Akiko; Kitami, Toshimori; Watanabe, Takashi; Ohara, Osamu; Yanaka, Noriyuki; Okada, Mariko; Shimoda, Michiko; Taniguchi, Masaru; Takemori, Toshitada.

In: International Immunology, Vol. 28, No. 6, 24.06.2016, p. 267-282.

Research output: Contribution to journalArticle

Kaji, T, Hijikata, A, Ishige, A, Kitami, T, Watanabe, T, Ohara, O, Yanaka, N, Okada, M, Shimoda, M, Taniguchi, M & Takemori, T 2016, 'CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation', International Immunology, vol. 28, no. 6, pp. 267-282. https://doi.org/10.1093/intimm/dxv071
Kaji, Tomohiro ; Hijikata, Atsushi ; Ishige, Akiko ; Kitami, Toshimori ; Watanabe, Takashi ; Ohara, Osamu ; Yanaka, Noriyuki ; Okada, Mariko ; Shimoda, Michiko ; Taniguchi, Masaru ; Takemori, Toshitada. / CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation. In: International Immunology. 2016 ; Vol. 28, No. 6. pp. 267-282.
@article{dcb145c96864409d9af4cf29dffd5f98,
title = "CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation",
abstract = "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.",
keywords = "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",
author = "Tomohiro Kaji and Atsushi Hijikata and Akiko Ishige and Toshimori Kitami and Takashi Watanabe and Osamu Ohara and Noriyuki Yanaka and Mariko Okada and Michiko Shimoda and Masaru Taniguchi and Toshitada Takemori",
year = "2016",
month = "6",
day = "24",
doi = "10.1093/intimm/dxv071",
language = "English (US)",
volume = "28",
pages = "267--282",
journal = "International Immunology",
issn = "0953-8178",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation

AU - Kaji, Tomohiro

AU - Hijikata, Atsushi

AU - Ishige, Akiko

AU - Kitami, Toshimori

AU - Watanabe, Takashi

AU - Ohara, Osamu

AU - Yanaka, Noriyuki

AU - Okada, Mariko

AU - Shimoda, Michiko

AU - Taniguchi, Masaru

AU - Takemori, Toshitada

PY - 2016/6/24

Y1 - 2016/6/24

N2 - 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.

AB - 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.

KW - Bcl6 (b-cell lymphoma 6)

KW - CD4 memory T-cell development

KW - Cognate interaction with non-GC B cells

KW - Memory B-cell recall response

KW - Stepwise transcriptional regulation

KW - T-follicular helper cells

UR - http://www.scopus.com/inward/record.url?scp=84973177459&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84973177459&partnerID=8YFLogxK

U2 - 10.1093/intimm/dxv071

DO - 10.1093/intimm/dxv071

M3 - Article

VL - 28

SP - 267

EP - 282

JO - International Immunology

JF - International Immunology

SN - 0953-8178

IS - 6

ER -