PD-1 tempers Tregs in chronic HCV infection
Henry Radziewicz, … , Richard M. Dunham, Arash Grakoui
Henry Radziewicz, … , Richard M. Dunham, Arash Grakoui
Published February 23, 2009
Citation Information: J Clin Invest. 2009;119(3):450-453. https://doi.org/10.1172/JCI38661.
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Commentary

PD-1 tempers Tregs in chronic HCV infection

Abstract

Adaptive T cell responses are critical for controlling infections with viruses such as HIV, HBV, and HCV. However, these responses must be carefully regulated because overly vigorous T cell activation can lead to excessive host tissue damage. T cell expression of the inhibitory receptor programmed death–1 (PD-1) and inhibition of effector T cells (Teffs) by CD4+Foxp3+ Tregs are among the many described mechanisms for achieving a balanced immune response. Although the signals that contribute to Teff function are well understood, less is known about the signals controlling Tregs. In this issue of the JCI, Franceschini et al. extend our understanding of how Tregs are modulated during chronic HCV infection by demonstrating that Treg proliferation is inhibited by PD-1 and that this inhibition is mediated by a potentially novel mechanism involving the prevention of IL-2–driven STAT-5 phosphorylation (see the related article beginning on page 551).

Authors

Henry Radziewicz, Richard M. Dunham, Arash Grakoui

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Figure 1

Pathway for inhibition of IL-2 signaling in Tregs by PD-1.

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Pathway for inhibition of IL-2 signaling in Tregs by PD-1. PD-1 signalin...
PD-1 signaling leads to dephosphorylation of molecules in the T cell activation cascade previously phosphorylated in response to TCR ligation. In this issue of the JCI, Franceschini et al. show that PD-1 signaling leads to inhibition of IL-2 signals in Tregs (5). (i) IL-2 signaling via the IL-2 receptor (IL-2R) induces STAT-5 phosphorylation (pSTAT-5). (ii) Dimerization and nuclear translocation of phosphorylated STAT-5 leads to increased proliferation of Tregs but also to PD-1 upregulation. (iii) Increased surface PD-1 expression inhibits STAT-5 phosphorylation (5), possibly via SHP2. ITSM, immunoreceptor tyrosine-based switch motif.