Ignoring type 1 interferons

Comment on Gil et al, page 987

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. ▪