PD1 is thought to inhibit T cells by suppressing T cell receptor-mediated signalling; whether PD1 ligation also upregulates the expression of genes that impair T cell function is not known. So, the authors analysed the gene expression profile of exhausted HIV-specific CD8+ T cells from individuals with active HIV disease and identified genes that are upregulated in these cells relative to HIV-specific CD8+ T cells from a small population of patients who can control replication of HIV (known as 'HIV controllers'). They found that the genes that were upregulated in exhausted CD8+ T cells included a subset of genes that were upregulated by PD1 ligation. These PD1 signature genes were also upregulated in exhausted lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells from infected mice, indicating that a consistent gene signature is induced by PD1 ligation in exhausted T cells in humans and mice.
The authors next determined what transcription factors were in this PD1 gene signature, as transcription factors have broad effects on the cell state. They identified only three: BATF, signal transducer and activator of transcription 1 (STAT1) and interferon-regulatory factor 9 (IRF9). As proof of principle, they looked at BATF, a negative regulator of the transcription factor activator protein 1 (AP1), and confirmed that BATF expression is upregulated by PD1 ligation in vitro and is increased in exhausted HIV-specific and LCMV-specific CD8+ T cells compared with functional CD8+ T cells.
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