Research ArticleImmunology

The Duration of T Cell Stimulation Is a Critical Determinant of Cell Fate and Plasticity

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Science Signaling  05 Nov 2013:
Vol. 6, Issue 300, pp. ra97
DOI: 10.1126/scisignal.2004217

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Signal Duration Controls T Cell Fate

CD4+ T cells are broadly classified into two groups: T helper (TH) cells, which mediate the immune response, and regulatory T (Treg) cells, which suppress immunity. Both cell types can arise from the differentiation of naïve CD4+ T cells stimulated through the T cell receptor (TCR) by antigen. Cell fate is thought to arise from differences in the intensity of the TCR signal, with strong TCR signals generating TH cells and weaker TCR signals generating Treg cells. Understanding how to manipulate T cell fate has implications for immunotherapies; for example, generating too few Treg cells can lead to autoimmunity, whereas generating too many Treg cells can suppress antitumor immunity. Miskov-Zivanov et al. developed a logical mathematical model of T cell differentiation focused on early stages of TCR signaling and found that differential activation of TCR signaling pathways by low and high doses of antigen was better modeled as changes in the duration, rather than the intensity, of TCR signaling. Their model predicted, and experiments confirmed, that there is a time window for signaling during which T cell fate is plastic and that varying the duration of stimulation controls the relative proportion of Treg and TH cells produced. The model also predicts that the TH cell phenotype stabilized more rapidly than did the Treg cell phenotype. Together, these data suggest that differential timing of TCR signaling events plays an important role in determining T cell fate.

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