The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs

J Clin Invest. 2005 Nov;115(11):3276-84. doi: 10.1172/JCI24685. Epub 2005 Oct 6.

Abstract

Little is known about the molecules that control the development and function of CD4+ CD25+ Tregs. Recently, it was shown that the transcription factor FOXP3 is necessary and sufficient for the generation of CD4+ CD25+ Tregs in mice. We investigated the capacity of FOXP3 to drive the generation of suppressive CD4+ CD25+ Tregs in humans. Surprisingly, although ectopic expression of FOXP3 in human CD4+ T cells resulted in induction of hyporesponsiveness and suppression of IL-2 production, it did not lead to acquisition of significant suppressor activity in vitro. Similarly, ectopic expression of FOXP3delta2, an isoform found in human CD4+ CD25+ Tregs that lacks exon 2, also failed to induce the development of suppressor T cells. Moreover, when FOXP3 and FOXP3delta2 were simultaneously overexpressed, although the expression of several Treg-associated cell surface markers was significantly increased, only a modest suppressive activity was induced. These data indicate that in humans, overexpression of FOXP3 alone or together with FOXP3delta2 is not an effective method to generate potent suppressor T cells in vitro and suggest that factors in addition to FOXP3 are required during the process of activation and/or differentiation for the development of bona fide Tregs.

Publication types

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

MeSH terms

  • Cell Differentiation* / genetics
  • Cells, Cultured
  • Cytokines / metabolism
  • Down-Regulation / genetics
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / physiology*
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation* / genetics
  • Mutation
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Protein Isoforms