Insufficient interleukin-12 signalling favours differentiation of human CD4(+) and CD8(+) T cells into GATA-3(+) and GATA-3(+) T-bet(+) subsets in humanized mice

Immunology. 2014 Oct;143(2):202-18. doi: 10.1111/imm.12304.

Abstract

Differentiation of CD4(+) T cells into type 1 or type 2 subsets is mediated by the expression of the opposing lineage defining transcription factors T-bet and GATA-3. However, the existence of GATA-3(+) T-bet(+) CD4(+) T cells in mice suggests functional plasticity of these subsets. Little is known about type 1 and type 2 plasticity of human T-cell subsets in vivo. Here, we show that in the xenogeneic environment of humanized mice, which lacks a functional immune-regulatory network, human CD4(+) and, notably, CD8(+) T cells preferentially differentiate into interleukin (IL)-4(+) GATA-3(+) and IL-4(+) interferon-γ(+) GATA-3(+) T-bet(+) subsets. Treatment with recombinant human IL-12 or expansion of IL-12-producing human dendritic cells in vivo reverted this phenotype and led to the down-regulation of GATA-3 expression. These changes also correlated with improved antiviral immune responses in humanized mice. In conclusion, our study shows the capacity of human CD4(+) and CD8(+) T cells for stable co-expression of GATA-3 and T-bet in humanized mice and reveals a critical role for IL-12 in regulating this phenotype.

Keywords: T-cell plasticity; humanized mice; interleukin-12.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / pathogenicity
  • Animals
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / virology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation*
  • Cell Lineage
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • GATA3 Transcription Factor / metabolism*
  • Hematopoietic Stem Cell Transplantation*
  • Host-Pathogen Interactions
  • Humans
  • Injections, Intraperitoneal
  • Interferon-gamma / metabolism
  • Interleukin-12 / administration & dosage
  • Interleukin-12 / metabolism*
  • Interleukin-4 / metabolism
  • Kinetics
  • Liver / immunology
  • Liver / metabolism
  • Liver / virology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Phenotype
  • Signal Transduction* / drug effects
  • T-Box Domain Proteins / metabolism*
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / virology
  • Transplantation, Heterologous
  • Viral Load

Substances

  • GATA3 Transcription Factor
  • GATA3 protein, human
  • IFNG protein, human
  • IL4 protein, human
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma