Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.1107778 on July 23, 2008

Published online before print July 23, 2008
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(Journal of Leukocyte Biology. 2008;84:973-980.)
© 2008 by Society for Leukocyte Biology

The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells

Thomas Y. Wuest*, Jami Willette-Brown*, Scott K. Durum{dagger} and Arthur A. Hurwitz*,1

* Tumor Immunity and Tolerance Section and
{dagger} Immunological Cytokine Research Group, Cancer and Inflammation Program, Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick, Frederick, Maryland, USA

1 Correspondence: Tumor Immunity and Tolerance Section, Cancer and Inflammation Program, Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick, P.O. Box B, Frederick, MD 21701, USA. E-mail: hurwitza{at}ncifcrf.gov

ABSTRACT

IL-2 is essential for CD4+CD25+forkhead box P3+ (FoxP3+) naturally occurring regulatory T cell (Treg) homeostasis and activation. Binding of IL-2 to its receptor leads to phosphorylation of STAT5, and binding of phosphorylated STAT5 to the foxp3 promoter increases foxp3 transcription, resulting in elevated levels of FoxP3 protein in Tregs. Transcriptional regulation by the elevated levels of FoxP3 is thought to be essential for the strong suppressor function seen in activated Tregs. IL-2 belongs to a family cytokines, which all depend on the common {gamma}-receptor chain ({gamma}c). Given the well-documented effects of IL-2 on Treg function, the effect of other IL-2 family cytokines (IL-7, -15, and -21) on Tregs was examined. We observed that IL-7 and IL-15 induce STAT5 phosphorylation and up-regulation of FoxP3 in Tregs. STAT5 activation correlated with enhanced viability. However, only in the presence of IL-2 did Tregs acquire potent suppressor function. This finding is surprising, as IL-15 as well as IL-2 use the same IL-2R βc and {gamma}c for signaling. In contrast, IL-21 activated STAT3 but did not activate STAT5 and had no effect on Treg viability, activation, or function. We therefore conclude that phosphorylation of STAT5, mediated through the IL-2R{gamma}, promotes Treg survival in a resting and activated state. However, activation of STAT5 alone in conjunction with TCR signaling is not sufficient for the induction of potent suppressor function in Tregs, as IL-7 and IL-15 are not capable of inducing potent Treg suppressor function.

Key Words: FoxP3 • IL-7 • IL-15 • CD25 • IL-21 • {gamma}c cytokines




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