GATA-3 transcriptional imprinting in Th2 lymphocytes: a mathematical model.
Immunological memory involves the fast recall of cytokine expression by T helper (Th) lymphocytes. Two distinct profiles of cytokine expression, Th1 and Th2, can be induced by antigen and polarizing signals during activation of naive Th cells and can subsequently be reexpressed on stimulation by antigen alone. The transcription factor GATA-3 induces Th2 development. GATA-3 is activated by the Th2-polarizing stimulus, IL-4, and has recently been observed to autoactivate its transcription. Based on these experimental data, we developed a mathematical model of GATA-3 expression that assumes independent activation of GATA-3 transcription by IL-4 and by GATA-3. Cooperativity of GATA-3 transcriptional activation is shown to create a threshold for autoactivation, resulting in the coexistence of two distinct GATA-3 expression states: a state of basal expression and a state of high expression sustained by autoactivation. Suprathreshold IL-4 signals induce a transition from basal to high GATA-3 expression. Thus, GATA-3 autoactivation creates a bistable system that can memorize a transient inductive signal. The model further predicts conditions under which the state of high GATA-3 expression can be abolished, which may extinguish the Th2 cytokine memory.
Höfer
Thomas
T
Theoretische Biophysik, Institut für Biologie, Humboldt-Universität Berlin, Invalidenstrasse 42, 10115 Berlin, Germany. thomas.hoefer@rz.hu-berlin.de
Nathansen
Holger
H
Löhning
Max
M
Radbruch
Andreas
A
Heinrich
Reinhart
R
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D050990:GATA3 Transcription Factor; D015870:Gene Expression; D006801:Humans; D007156:Immunologic Memory; D008433:Mathematics; D008954:Models, Biological; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators