Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Aging Cell. 2019 Aug;18(4):e12957. doi: 10.1111/acel.12957. Epub 2019 Jul 1.

Abstract

With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T-cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T-cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging-associated changes in the transcription factor profile favor TH9 commitment.

Keywords: T-cell lineage differentiation; aging; immunosenescence; interleukin 9; multipotency; transforming growth factor β.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Blood Donors
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / genetics*
  • Female
  • HEK293 Cells
  • Healthy Volunteers
  • Humans
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / metabolism*
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Interleukin-9 / metabolism
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Proteoglycans / genetics
  • Proteoglycans / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Proto-Oncogene Proteins c-bcl-6 / metabolism*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Trans-Activators / metabolism*
  • Transfection
  • Young Adult

Substances

  • BATF protein, human
  • BCL6 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • IL9 protein, human
  • Inhibitor of Differentiation Proteins
  • Interferon Regulatory Factors
  • Interleukin-9
  • Neoplasm Proteins
  • Proteoglycans
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, Antigen, T-Cell
  • Receptors, Transforming Growth Factor beta
  • Trans-Activators
  • interferon regulatory factor-4
  • proto-oncogene protein Spi-1
  • betaglycan
  • ID3 protein, human