Comment on Gil et al, page
Modulation of STAT1 levels in virus-specific CD8 T cells allows rapid clonal expansion in the presence of type I interferons.
In response to an acute viral infection, naive CD8 T cells triggered by antigen undergo a massive expansion that peaks approximately one week later in most infection models. This antigen-specific CD8 T-cell population is essential for clearance of many viral pathogens; prior to their appearance virus spread is held in check, but not contained, by innate immune defenses. Type 1 (α and β) interferons (IFNs), produced within hours of infection, play a major role in the earliest host response by inducing a large number of genes that can inhibit virus replication in susceptible cell types. Beyond these direct antiviral effects, IFN-α/β serve many additional functions, such as stimulating maturation of antigen-presenting dendritic cells and limiting nonspecific immune-cell proliferation.
The signaling pathway used by type 1 IFNs has been very well characterized. When activated by ligand binding, the receptor-associated tyrosine kinases, TYK2 and JAK1, phosphorylate the IFN-α/β receptor subunit 1, which then serves as a binding site for STAT2. Tyrosine phosphorylation of bound STAT2 allows STAT1 binding and its activation by phosphorylation on Y701. The activated STAT proteins are then able to form the heterotrimeric ISGF3 (interferon-stimulated gene factor 3) complex, composed of STAT1, STAT2, and IRF9, which moves into the nucleus and mediates transcriptional up-regulation of IFN-responsive genes. But while the details of IFN-α/β signaling are well understood at the level of the single cell, the larger problem of explaining how the various in vivo effects of IFN-α/β are simultaneously regulated remains. In this issue, a paper by Gil and colleagues shines new light onto this larger question by asking how antigen-specific T cells can proliferate rapidly in the presence of type 1 IFN concentrations sufficient to inhibit T-cell growth. The authors address this paradox by demonstrating first that the antiproliferative effects of IFN-α/β are STAT1 dependent and secondly, that as infection progresses, STAT1 levels decline in the antigen-specific CD8 T-cell subset. This is in contrast to other splenic leukocytes, including nonproliferating CD8 T cells, in which STAT1 levels are enhanced (see figure). Although this group has previously shown that type 1 IFN effects will vary depending on the ratio of STAT1 and STAT4 expression,1 this is the first demonstration of STAT1 modulation within a particular cell type in the course of a virus infection. Down-regulation of STAT1 protein levels following activation of CD8 lymphocytes through the T-cell receptor allows these cells to ignore type 1 IFNs and continue to expand even in their presence. This is consistent with a recent report that type 1 IFNs promote rather than inhibit the proliferative response to mitogenic stimuli by T cells lacking either Stat1 or Stat2.2 Thus, the nuanced regulation of JAK/STAT signaling in vivo that is revealed by Gil et al resolves a number of apparent contradictions by uncovering yet another layer of complexity in the host IFN response to viral pathogens. ▪
Virus infection is quickly followed by production of type I IFNs. These cytokines will antagonize viral replication but also act to inhibit T-cell expansion in a STAT1 dependent manner (top). Gil et al now show that rapidly dividing (CSFE10), virus-specific T cells overcome this block to proliferation by down-modulating the level of STAT1 protein available for transducing signals from the IFN-αβ receptor (bottom). Illustration by Kenneth Probst.
Virus infection is quickly followed by production of type I IFNs. These cytokines will antagonize viral replication but also act to inhibit T-cell expansion in a STAT1 dependent manner (top). Gil et al now show that rapidly dividing (CSFE10), virus-specific T cells overcome this block to proliferation by down-modulating the level of STAT1 protein available for transducing signals from the IFN-αβ receptor (bottom). Illustration by Kenneth Probst.
