Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets.
Naive CD4+ T cells activated through TCR/CD28 under Th1 or Th2 conditions expressed canonical cytokine patterns irrespective of cell division. Only cells that had divided fewer than four times were capable of reexpressing alternative cytokines when restimulated under opposing conditions. Although T cells transcribed both IFN-gamma and IL-4 within hours in a Stat4-/Stat6-independent manner, neither T-bet nor GATA-3 was induced optimally without Stat signals, and polarized cytokine expression was not sustained. Cytokine genes were positioned apart from heterochromatin in resting T cell nuclei, consistent with rapid expression. After polarization, the majority of silenced cytokine alleles were repositioned to heterochromatin. Naive T cells transit through sequential stages of cytokine activation, commitment, silencing, and physical stabilization during polarization into differentiated effector subsets.
Grogan
J L
JL
Howard Hughes Medical Institute, University of California, San Francisco, 94143, San Francisco, CA, USA.
Mohrs
M
M
Harmon
B
B
Lacy
D A
DA
Sedat
J W
JW
Locksley
R M
RM
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor; D017353:Gene Deletion; D020868:Gene Silencing; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D015848:Interleukin-5 / Q000235:genetics; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D019076:Transgenes / Q000235:genetics; D000098815:T-bet Transcription Factor
D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006570:Heterochromatin; D015848:Interleukin-5; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor