Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes

Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G and Sallusto F
Source: Nat Immunol
Publication Date: (2003)
Issue: 4: 78-86
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
The authors studied memory and flexibility of differentiated T lymphocytes and their ability to switch between the T helper cell type 1 (TH1) and T helper type 2 (TH2) lineage. Involved in commitment to either lineage is the transcription factor T-bet. To further elucidate the role of T-bet, TH2 cells were nucleofected with an expression vector encoding T-bet and analyzed for TH1 and TH2 specific cytokine production after stimulation. Overexpression of T-bet caused a re-commitment of the TH2 to the TH1 lineage. Between 12-22% of TH2 cells expressing ectopic T-bet rapidly acquired the ability to produce IFN-gamma (TH1 specific response) indicating that T-bet expression plays a major role in commitment to TH2 lineage.
CD4+ T cell priming under T helper type I (T(H)1) or T(H)2 conditions gives rise to polarized cytokine gene expression. We found that in these conditions human naive T cells acquired stable histone hyperacetylation at either the Ifng or Il4 promoter. Effector memory T cells showed polarized cytokine gene acetylation patterns in vivo, whereas central memory T cells had hypoacetylated cytokine genes but acquired polarized acetylation and expression after appropriate stimulation. However, hypoacetylation of the nonexpressed cytokine gene did not lead to irreversible silencing because most T(H)1 and T(H)2 cells acetylated and expressed the alternative gene when stimulated under opposite T(H) conditions. Such cytokine flexibility was absent in a subset of T(H)2 cells that failed to up-regulate T-bet and to express interferon-gamma when stimulated under T(H)1 conditions. Thus, most human CD4+ T cells retain both memory and flexibility of cytokine gene expression.